Welcome to our monthly trawl for developmental biology (and related) preprints.

The preprints this month are hosted on bioRxiv, arXiv and preprints.org – use these links to get to the section you want.

Developmental biology

• Patterning & signalling
• Morphogenesis & mechanics
• Genes & genomes
• Stem cells, regeneration & disease modelling
• Plant development
• Evo-devo

Cell Biology

Modelling

Reviews

Tools & Resources

Research practice & education

Developmental biology

| Patterning & signalling

An RNA-based feed-forward mechanism ensures motor switching in oskar mRNA transport
Imre Gáspár, Ly Jane Phea, Mark A. McClintock, Simone Heber, Simon L. Bullock, Anne Ephrussi

Quantitative imaging in whole-mount zebrafish embryos traces morphogen gradient maintenance and noise propagation in BMP signaling
Xu Wang, Linlin Li, Ye Bu, Yixuan Liu, Tzu-Ching Wu, David M. Umulis

The Drosophila RNA binding protein Nab2 patterns dendritic arbors and axons via the planar cell polarity pathway
Edwin B. Corgiat, Sara M. List, J. Christopher Rounds, Dehong Yu, Ping Chen, Anita H. Corbett, Kenneth H. Moberg

Netrins and receptors control Drosophila optic lobe organization and transmedullary neuron axon targeting
Yu Zhang, Scott Lowe, Xin Li

Target of Rapamycin drives unequal responses to essential amino acid depletion in egg laying
André N. Alves, Carla M. Sgrò, Matthew D. Piper, Christen K. Mirth

Live imaging YAP signaling in mouse embryo development
Bin Gu, Brian Bradshaw, Min Zhu, Yu Sun, Sevan Hopyan, Janet Rossant

The expression of essential selenoproteins during zebrafish development requires SECIS binding protein 2-like
Nora T. Kiledjian, Rushvi Shah, Michael B. Vetick, Paul R. Copeland

Adar1 deletion causes degeneration of exocrine pancreas via Mavs-dependent interferon signaling
Dhwani N. Rupani, Robert W. Cowan, Fredrik I. Thege, Vidhi Chandra, Sonja M. Wörmann, Hajar Rajaei, Prerna Malaney, Olivereen Le Roux, Sara L. Manning, Jack Hashem, Jennifer Bailey-Lundberg, Florencia McAllister, Andrew D. Rhim

Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
Tamer Ali, Sandra Rogala, Maria-Theodora Melissari, Sandra Währisch, Bernhard G Herrmann, Phillip Grote

A microRNA cluster downstream of the selector gene Fezf2 coordinates fate specification with dendritic branching in cortical neurons
Asha Iyer, Verl B Siththanandan, Victoria Lu, Ramesh Nair, Lee O. Vaasjo, Maria J Galazo, Suzanne Tharin

A life cycle alteration can correct molting defects in Caenorhabditis elegans
Shaonil Binti, Rosa V. Melinda, Braveen B. Joseph, Phil Edeen, Sam D. Miller, David S. Fay

Mechanisms underlying microglial colonization of developing neural retina in zebrafish
Nishtha Ranawat, Ichiro Masai

A comprehensive series of temporal transcription factors in the fly visual system
Nikolaos Konstantinides, Anthony M. Rossi, Aristides Escobar, Liébaut Dudragne, Yen-Chung Chen, Thinh Tran, Azalia Martinez Jaimes, Mehmet Neset Özel, Félix Simon, Zhiping Shao, Nadejda M. Tsankova, John F. Fullard, Uwe Walldorf, Panos Roussos, Claude Desplan

Live imaging YAP signaling in mouse embryo development
Bin Gu, Brian Bradshaw, Min Zhu, Yu Sun, Sevan Hopyan, Janet Rossant

TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling
Sushama Sivakumar, Shutao Qi, Ningyan Cheng, Adwait A. Sathe, Mohammed Kanchwala, Ashwani Kumar, Bret M. Evers, Chao Xing, Hongtao Yu

TGFβ signaling is required for sclerotome resegmentation during development of the spinal column in Gallus gallus
Sade W. Clayton, Ronisha McCardell, Rosa Serra

A neural progenitor mitotic wave is required for asynchronous axon outgrowth and morphology
Jérôme Lacoste, Hédi Soula, Angélique Burg, Agnès Audibert, Pénélope Darnat, Michel Gho, Sophie Louvet-Vallée

Selective YAP activation in Procr cells is essential for ovarian stem/progenitor expansion and epithelium repair
Jingqiang Wang, Lingli He, Zhiyao Xie, Wentao Yu, Lanyue Bai, Zuoyun Wang, Yi Lu, Chunye Liu, Junfen Fu, Lei Zhang, Yi Arial Zeng

Omics profiling identifies MAPK/ERK pathway as a gatekeeper of nephron progenitor metabolism
Hyuk Nam Kwon, Kristen Kurtzeborn, Xing Jin, Abigail Loh, Nathalie Escande-Beillard, Bruno Reversade, Sunghyouk Park, Satu Kuure

How do avian embryos resume development following diapause? A new role for TGF-β in regulating pluripotency-related genes
Narayan Pokhrel, Olga Genin, Dalit Sela-Donenfeld, Yuval Cinnamon

A non-transcriptional function of Yap orchestrates the DNA replication program
Rodrigo Meléndez García, Olivier Haccard, Albert Chesneau, Hemalatha Narassimprakash, Jérôme E Roger, Muriel Perron, Kathrin Marheineke, Odile Bronchain

Pre-implantation mouse embryo movement under hormonally altered conditions
Hannah Lufkin, Diana Flores, Zachary Raider, Manoj Madhavan, Madeline Dawson, Anna Coronel, Dhruv Sharma, Ripla Arora

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia
Alberto Dinarello, Riccardo Massimiliano Betto, Chiara Cioccarelli, Linda Diamante, Giacomo Meneghetti, Margherita Peron, Annachiara Tesoriere, Claudio Laquatra, Natascia Tiso, Graziano Martello, Francesco Argenton

CLASS-II KNOX genes coordinate spatial and temporal patterns of the tomato ripening
Alexandra Keren-Keiserman, Amit Shtern, Daniel Chalupowicz, Chihiro Furumizu, John Paul Alvarez, Ziva Amsalem, Tzahi Arazi, Sharon Tuvia-Alkalai, Idan Efroni, Elazar Fallik, Alexander Goldshmidt

Connexinplexity: The spatial and temporal expression of connexin genes during vertebrate organogenesis
Rachel M. Lukowicz-Bedford, Dylan R. Farnsworth, Adam C. Miller

PDFGRα+ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling
Nicholas Moskwa, Ayma Mahmood, Deirdre A. Nelson, Amber L. Altrieth, Paolo Forni, Melinda Larsen

GPI-anchored FGF directs cytoneme-mediated bidirectional signaling to self-regulate tissue-specific dispersion
Lijuan Du, Alex Sohr, Yujia Li, Sougata Roy

Mechanisms underlying the cooperation between loss of epithelial polarity and Notch signaling during neoplastic growth in Drosophila
Rémi Logeay, Charles Géminard, Patrice Lassus, Miriam Rodríguez-Vázquez, Diala Kantar, Lisa Héron-Milhavet, Bettina Fischer, Sarah J. Bray, Jacques Colinge, Alexandre Djiane

Using light-sheet microscopy to study spontaneous activity in the developing lateral-line system
Qiuxiang Zhang, Katie Kindt

SELENOT deficiency alters projection neuron migration during corticogenesis in mice
Emmanuelle Carpentier, Anthony Falluel-Morel, Lisa Brunet, Magalie Bénard, David Godefroy, Loubna Boukhzar, Arnaud Arabo, Youssef Anouar

SRSF3 is a key regulator of epicardial formation
Irina-Elena Lupu, Andia N. Redpath, Nicola Smart

Mural cell SRF controls pericyte migration, vessel patterning and blood flow
Michael Martin Orlich, Rodrigo Diéguez-Hurtado, Regine Muehlfriedel, Vithiyanjali Sothilingam, Hartwig Wolburg, Cansu Ebru Oender, Pascal Woelffing, Christer Betsholtz, Konstantin Gaengel, Mathias Seeliger, Ralf H. Adams, Alfred Nordheim

Charting ESCRT function reveals distinct and non-compensatory roles in blood progenitor maintenance and lineage choice in Drosophila
Arindam Ray, Yashashwinee Rai, Maneesha S Inamdar

Reemployment of Kupffer’s vesicle cells into axial and paraxial mesoderm via transdifferentiation
Takafumi Ikeda, Kiichi Inamori, Toru Kawanishi, Hiroyuki Takeda

Retinoid-X Receptor Agonists Increase Thyroid Hormone Competence in Lower Jaw Remodeling of Pre-Metamorphic Xenopus laevis tadpoles
Brenda J. Mengeling, Lara F. Vetter, J. David Furlow

ESR2 regulates indian hedgehog signaling in neonatal rat ovary
Iman Dilower, V. Praveen Chakravarthi, Eun B. Lee, Subhra Ghosh, Shaon Borosha, Richita Roy, Saeed Masumi, Anohita Paul, Hindole Ghosh, Michael W. Wolfe, M. A. Karim Rumi

Ikaros family proteins regulate developmental windows in the mouse retina through convergent and divergent transcriptional programs
Awais Javed, Pierre Mattar, Allie Cui, Michel Cayouette

Maternal parity affects Day 8 embryo gene expression in old mares
Emilie Derisoud, Luc Jouneau, Clothilde Gourtay, Anne Margat, Catherine Archilla, Yan Jaszczyszyn, Rachel Legendre, Nathalie Daniel, Nathalie Peynot, Michèle Dahirel, Laurie Briot, Frédéric De Geoffroy, Véronique Duranthon, Pascale Chavatte-Palmer

Cell-state transitions and collective cell movement generate an endoderm-like region in gastruloids
Ali Hashmi, Sham Tlili, Pierre Perrin, Alfonso Martinez-Arias, Pierre-François Lenne

The molecular logic of synaptic wiring at the single cell level
Jessica Velten, Rashi Agarwal, Patrick van Nierop, Katrin Domsch, Lena Bognar, Malte Paulsen, Lars Velten, Ingrid Lohmann

Coupling adipose tissue architecture and metabolism via cytoophidia
Jingnan Liu, Yuanbing Zhang, Youfang Zhou, Qiao-Qi Wang, Kang Ding, Suwen Zhao, Pengfei Lu, Ji-Long Liu

From the formation of embryonic appendages to the color of wings: Conserved and novel roles of aristaless1 in butterfly development
Erick X. Bayala, Nicholas VanKuren, Darli Massardo, Marcus Kronforst

CTP synthase does not form cytoophidia in Drosophila interfollicular stalks
Zheng Wu, Ji-Long Liu

Neighbor-specific gene expression revealed from physically interacting cells during mouse embryonic development
Junil Kim, Michaela Mrugala Rothová, Linbu Liao, Siyeon Rhee, Guangzheng Weng, Eyal David, Ido Amit, Morteza Chalabi Hajkarim, Joshua M. Brickman, Kyoung Jae Won

A Notch-dependent transcriptional mechanism controls expression of temporal patterning factors in Drosophila medulla
Alokananda Ray, Xin Li

Prdm16 and Notch functionally and physically interact during artery development
Manu Beerens, Jore Van Wauwe, Sander Craps, Margo Daems, KC Ashmita, Chris Finck, Shane Wright, Nicholas D. Leigh, Calum A. MacRae, Aernout Luttun

The RNA helicase DDX6 controls early mouse embryogenesis by repressing aberrant inhibition of BMP signaling through miRNA-mediated gene silencing
Jessica Kim, Masafumi Muraoka, Rieko Ajima, Hajime Okada, Atsushi Toyoda, Hiroshi Mori, Yumiko Saga

IGF1 Signaling in Temporomandibular Joint Fibrocartilage Stem Cells Regulates Cartilage Growth and Homeostasis in Mice
Ruiye Bi, Xueting Luo, Qianli Li, Peiran Li, Yi Fan, Binbin Ying, Songsong Zhu

| Morphogenesis & mechanics

Spontaneous rotations in epithelia as an interplay between cell polarity and RhoA activity at boundaries
S. Lo Vecchio, O. Pertz, M. Szopos, L. Navoret, D. Riveline

The roles of distinct Ca2+ signaling mediated by Piezo and inositol triphosphate receptor (IP3R) in the remodeling of E-cadherin during cell dissemination
Alejandra J.H. Cabrera, Barry M. Gumbiner, Young V. Kwon

Cell Wall Biochemistry Drives Pollen Tube Mechanics and Affects Growth Rate
Hannes Vogler, Gautam Munglani, Tohnyui Ndinyanka Fabrice, Christian Draeger, Jan T. Burri, Christof Eichenberger, J. Paul Knox, Jean Claude Mollet, Bradley J. Nelson, Hans J. Herrmann, Christoph Ringli, Ueli Grossniklaus

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair
Susana Lechuga, Alexander X. Cartagena-Rivera, Afshin Khan, Bert I. Crawford, Vani Narayanan, Daniel E. Conway, Jaakko Lehtimäki, Pekka Lappalainen, Florian Rieder, Michelle S. Longworth, Andrei I. Ivanov

Multifaceted control of E-cadherin dynamics by the Adaptor Protein Complex 1 during epithelial morphogenesis
Miguel Ramírez Moreno, Katy Boswell, Helen L. Casbolt, Natalia A. Bulgakova

Calcium fluctuations drive morphological patterning at the onset of Hydra morphogenesis
Erez Braun

Integration of vascular progenitors into functional blood vessels represents a novel mechanism of vascular growth
Sanjeeva Metikala, Michael Warkala, Satish Casie Chetty, Brendan Chestnut, Elizabeth Plender, Olivia Nester, Sophie Astrof, Saulius Sumanas

A lateral protrusion latticework connects neuroepithelial cells and is regulated during neurogenesis
Ioannis Kasioulis, Alwyn Dady, John James, Alan Prescott, Pamela A. Halley, Kate G. Storey

The C. elegans gonadal sheath Sh1 cells extend asymmetrically over a differentiating germ cell population in the proliferative zone
Xin Li, Noor Singh, Camille Miller, India Washington, Bintou Sosseh, Kacy Lynn Gordon

Optogenetic dissection of the roles of actomyosin in the mechanics underlying tissue fluidity
R. Marisol Herrera-Perez, Christian Cupo, Cole Allan, Alicia B. Dagle, Karen E. Kasza

Visceral organ morphogenesis via calcium-patterned muscle contractions
Noah P. Mitchell, Dillon Cislo, Suraj Shankar, Yuzheng Lin, Boris I. Shraiman, Sebastian J. Streichan

Cell cycle difference creates cortical tension difference that separates germ layer fates
Naohito Takatori, Yuuya Tachiki

Morphological aspects of opossum (Didelphis aurita) pancreas during intramarsupial development
Priscila Izabel Santos de Tótaro, Tarcísio De Souza Duarte, Clóvis Andrade Neves, Cláudio Cesar Fonseca, Silene Souza Rodrigues Sartori

Esrrγa regulates nephron development and ciliogenesis by controlling prostaglandin synthesis and cooperation with Ppargc1a
Hannah M. Wesselman, Ana L. Flores-Mireles, Rebecca A. Wingert

Competition for endothelial cell polarity drives vascular morphogenesis
Pedro Barbacena, Maria Dominguez-Cejudo, Catarina G. Fonseca, Manuel Gómez-González, Laura M. Faure, Georgia Zarkada, Andreia A. Pena, Anna Pezzarossa, Daniela Ramalho, Ylenia Giarratano, Marie Ouarné, David Barata, Isabela Fortunato, Lenka H. Misiková, Ian Mauldin, Yulia Carvalho, Xavier Trepat, Pere Roca-Cusachs, Anne Eichmann, Miguel O. Bernabeu, Cláudio A. Franco

Vertebrate hemicentin-1 interacts physically and genetically with nidogen-2
Jin-Li Zhang, Stefania Richetti, Thomas Ramezani, Daniela Welcker, Steffen Lütke, Hans-Martin Pogoda, Julia Hatzold, Frank Zaucke, Douglas R. Keene, Wilhelm Bloch, Gerhard Sengle, Matthias Hammerschmidt

Tetraspanin Cd9b and Cxcl12a/Cxcr4b have a synergistic effect on the control of collective cell migration
KS Marsay, S Greaves, H Mahabaleshwar, CM Ho, H Roehl, PN Monk, T. J. Carney, LJ Partridge

The developing kidney actively negotiates geometric packing conflicts to avoid defects
Louis S. Prahl, John M. Viola, Jiageng Liu, Alex J. Hughes

An interplay between cellular growth and atypical fusion defines morphogenesis of a modular glial niche
Maria Alexandra Rujano, David Briand, Bojana Ðelić, Pauline Spéder

Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis
Ester Comellas, Johanna E Farkas, Giona Kleinberg, Katlyn Lloyd, Thomas Mueller, Timothy J Duerr, Jose J Muñoz, James R Monaghan, Sandra J Shefelbine

Patterned mechanical feedback establishes a global myosin gradient
Hannah J. Gustafson, Nikolas Claussen, Stefano De Renzis, Sebastian J. Streichan

Tissue-specific inhibition of protein sumoylation uncovers diverse SUMO functions during C. elegans vulval development
Aleksandra Fergin, Gabriel Boesch, Nadja R. Greter, Simon Berger, Alex Hajnal

Spatiotemporal expression of regulatory kinases directs the transition from mitosis to cellular morphogenesis
Shuo Yang, Jennifer McAdow, Yingqiu Du, Jennifer Trigg, Paul H. Taghert, Aaron N. Johnson

Effective mechanical potential of cell–cell interaction explains basic structures of three-dimensional morphogenesis
Hiroshi Koyama, Hisashi Okumura, Atsushi M. Ito, Tetsuhisa Otani, Kazuyuki Nakamura, Kagayaki Kato, Toshihiko Fujimori

Mechanics of cell integration in vivo
Guilherme B. Ventura, Aboutaleb Amiri, Raghavan Thiagarajan, Mari Tolonen, Amin Doostmohammadi, Jakub Sedzinski

| Genes & genomes

Interpreting ruminant specific conserved non-coding elements by developmental gene regulatory network
Xiangyu Pan, Zhaoxia Ma, Xinqi Sun, Hui Li, Tingting Zhang, Chen Zhao, Nini Wang, Rasmus Heller, Wing Hung Wong, Wen Wang, Yu Jiang, Yong Wang

Mitochondrial DNA variants segregate during human preimplantation development into genetically different cell lineages that are maintained postnatally
Joke Mertens, Marius Regin, Neelke De Munck, Edouard Couvreu de Deckersberg, Florence Belva, Karen Sermon, Herman Tournaye, Christophe Blockeel, Hilde Van de Velde, Claudia Spits

Nucleolar-based Dux repression is essential for 2-cell stage exit
Sheila Q. Xie, Bryony J. Leeke, Chad Whidling, Ryan T. Wagner, Ferran Garcia-Llagostera, Paul Chammas, Nathan T-F. Cheung, Dirk Dormann, Michael T. McManus, Michelle Percharde

Cellular remodeling and JAK inhibition promote zygotic gene expression in the Ciona germline
Naoyuki Ohta, Lionel Christiaen

A feedback loop between heterochromatin and the nucleopore complex controls germ-cell to oocyte transition during Drosophila oogenesis
Kahini Sarkar, Noor M Kotb, Alex Lemus, Elliot T Martin, Alicia McCarthy, Justin Camacho, Ayman Iqbal, Alex M. Valm, Morgan A Sammons, Prashanth Rangan

An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype
Kathleen C. Keough, Parisha P. Shah, Ketrin Gjoni, Garrett T. Santini, Nadeera M. Wickramasinghe, Carolyn E. Dundes, Ashley Karnay, Angela Chen, Rachel E.A. Salomon, Patrick J. Walsh, Son C. Nguyen, Sean Whalen, Eric F. Joyce, Kyle M. Loh, Nicole Dubois, Katherine S. Pollard, Rajan Jain

ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity
Vasiliki Theodorou, Aikaterini Stefanaki, Minas Drakos, Dafne Triantafyllou, Christos Delidakis

Comprehensive identification of fetal cis-regulatory elements in the human genome by single-cell multi-omics analysis
Hao Yu, Na Ai, Ping Peng, Yuwen Ke, Xuepeng Chen, Yun Li, Ting Zhao, Shan Jiang, Jiang Liu, Lan Jiang

Pan-primate DNA methylation clocks
Steve Horvath, Amin Haghani, Joseph A. Zoller, Ake T. Lu, Jason Ernst, Matteo Pellegrini, Anna J. Jasinska, Julie A. Mattison, Adam B. Salmon, Ken Raj, Markus Horvath, Kimberly C. Paul, Beate R. Ritz, Todd R. Robeck, Maria Spriggs, Erin E. Ehmke, Susan Jenkins, Cun Li, Peter W. Nathanielsz

Trim41 is essential for preventing X chromosome chaotic synapsis in male mice
Seiya Oura, Toshiaki Hino, Takashi Satoh, Taichi Noda, Takayuki Koyano, Ayako Isotani, Makoto Matsuyama, Shizuo Akira, Kei-ichiro Ishiguro, Masahito Ikawa

Reciprocal zebrafish-medaka hybrids reveal maternal control of zygotic genome activation timing
Krista R. Gert, Luis Enrique Cabrera Quio, Maria Novatchkova, Yixuan Guo, Bradley R. Cairns, Andrea Pauli

Maternally-inherited anti-sense piRNAs antagonize transposon expression in teleost embryos
Yixuan Guo, Krista R. Gert, Svetlana Lebedeva, Magdalena E. Potok, Candice L. Wike, Edward J. Grow, René F. Ketting, Andrea Pauli, Bradley R. Cairns

STAG2 promotes the myelination transcriptional program in oligodendrocytes
Ningyan Cheng, Mohammed Kanchwala, Bret M. Evers, Chao Xing, Hongtao Yu

The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless
Rui Chen, Xiaobing Deng, Sijun Zhu

Parental genomes segregate into different blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts
Tine De Coster, Heleen Masset, Olga Tšuiko, Maaike Catteeuw, Nicolas Dierckxsens, Sophie Debrock, Karen Peeraer, Katrien Smits, Ann Van Soom, Joris Robert Vermeesch

Identification and characterization of BEND2 as a novel and key regulator of meiosis during mouse spermatogenesis
Longfei Ma, Dan Xie, Xiwen Lin, Hengyu Nie, Jian Chen, Chenxu Gao, Shuguang Duo, Chunsheng Han

Loss of histone methyltransferase SETD1B in oogenesis results in the redistribution of genomic histone 3 lysine 4 trimethylation
Courtney W. Hanna, Jiahao Huang, Christian Belton, Susanne Reinhardt, Andreas Dahl, Simon Andrews, A. Francis Stewart, Andrea Kranz, Gavin Kelsey

Feedforward regulatory logic underlies robustness of the specification-to-differentiation transition and fidelity of terminal cell fate during C. elegans endoderm development
Chee Kiang Ewe, Erica M. Sommermann, Josh Kenchel, Sagen E. Flowers, Morris F. Maduro, Joel H. Rothman

Interchromosomal interaction of homologous Stat92E alleles regulates transcriptional switch during stem-cell differentiation
Matthew Antel, Madona Masoud, Romir Raj, Ziwei Pan, Sheng Li, Barbara G. Mellone, Mayu Inaba

Cellular remodeling and JAK inhibition promote zygotic gene expression in the Ciona germline
Naoyuki Ohta, Lionel Christiaen

Defining the Transcriptional and Epigenetic Basis of Organotypic Endothelial Diversity in the Developing and Adult Mouse
Manuel E. Cantu Gutierrez, Matthew C. Hill, Gabrielle Largoza, James F. Martin, Joshua D. Wythe

Sperm Histone H3 Lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction
Anne-Sophie Pepin, Christine Lafleur, Romain Lambrot, Vanessa Dumeaux, Sarah Kimmins

The distinct effects of MEK and GSK3 inhibition upon the methylome and transcriptome of mouse embryonic stem cells
Julia Spindel, Christel Krueger, Felix Krueger, Evangelia K. Papachristou, Kamal Kishore, Clive S. D’Santos, Wolf Reik

Investigation of Human Endogenous Retrovirus-K (ERVK) Expression and Function in Normal Placentation and Preterm Pregnancy
Jimi L. Rosenkrantz, Michael Martinez, Adithi Mahankali, Lucia Carbone, Shawn L. Chavez

Genome-wide mapping of histone modification H3K4me3 in bovine oocytes and early embryos
Yanna Dang, Lei Luo, Yan Shi, Shuang Li, Shaohua Wang, Kun Zhang

Mouse CHD4-NURD is required for neonatal spermatogonia survival and normal gonad development
Rodrigo O. de Castro, Luciana Previato, Agustin Carbajal, Victor Goitea, Courtney T. Griffin, Roberto J. Pezza

Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors
Sruti Patoori, Samantha Barnada, Marco Trizzino

TFAP2 paralogs pioneer chromatin access for MITF and directly inhibit genes associated with cell migration
Colin Kenny, Ramile Dilshat, Hannah Seberg, Eric Van Otterloo, Gregory Bonde, Annika Helverson, Eiríkur Steingrímsson, Robert A. Cornell

Non-random sister chromatid segregation mediates rDNA copy number maintenance in Drosophila
George J. Watase, Yukiko M. Yamashita

Intron dynamics reveal principles of gene regulation during the maternal-to-zygotic transition
Kent Riemondy, Jesslyn C. Henriksen, Olivia S. Rissland

Critical role of H3K27 methylation in cell fate determination of two cell lineages in male gametophyte
Xiaorong Huang, Meng-Xiang Sun

Dynamics of sex-biased gene expression during development in the stick insect Timema californicum
Djordjevic Jelisaveta, Dumas Zoé, Robinson-Rechavi Marc, Schwander Tanja, Parker Darren James

A Unified Genomic Mechanism of Cell-Fate Change
Masa Tsuchiya, Alessandro Giuliani, Giovanna Zimatore, Jekaterina Erenpreisa, Kenichi Yoshikawa

Analysis of transcriptional changes associated with pubertal development
Justyna Resztak, Jane Choe, Julong Wei, Rachel Bruinsma, Russell Houpt, Adnan Alazizi, Henriette E. Mair-Meijers, Richard B. Slatcher, Samuele Zilioli, Roger Pique-Regi, Francesca Luca

| Stem cells, regeneration & disease modelling

Identification and Characterization of Stem Cells in Mammalian Esophageal Stratified Squamous Epithelia
Yanan Yang, Guodong Deng, Lili Qiao, Hui Yuan, Xiaohong Yu, Lei Xu, Shih-Hsin Lu, Wei Jiang, Xiying Yu

Trisomy 21 induces pericentrosomal crowding disrupting early stages of primary ciliogenesis and mouse cerebellar development
Cayla E Jewett, Bailey L McCurdy, Eileen T O’Toole, Katherine S Given, Carrie H Lin, Valerie Olsen, Whitney Martin, Laura G Reinholdt, Joaquin M Espinosa, Kelly D Sullivan, Wendy B Macklin, Rytis Prekeris, Chad G Pearson

Pluripotency-Independent Induction of Human Trophoblast Stem Cells from Fibroblasts
Moriyah Naama, Ahmed Radwan, Valery Zayat, Shulamit Sebban, Moran Rahamim, Rachel Lasry, Mohammad Jaber, Ofra Sabag, Hazar Yassen, Dana Orzech, Areej Khatib, Silvina Epsztejn-Litman, Michal Novoselsky-Persky, Kirill Makedonski, Noy Deri, Debra Goldman-Wohl, Howard Cedar, Simcha Yagel, Rachel Eiges, Yosef Buganim

MTG16 (CBFA2T3) represses E protein-dependent transcription to regulate colonic secretory cell differentiation, epithelial regeneration, and tumorigenesis
Rachel E. Brown, Justin Jacobse, Shruti A. Anant, Koral M. Blunt, Bob Chen, Paige N. Vega, Chase T. Jones, Jennifer M. Pilat, Frank Revetta, Aidan H. Gorby, Kristy R. Stengel, Yash A. Choksi, Kimmo Palin, M. Blanca Piazuelo, M. Kay Washington, Ken S. Lau, Jeremy A. Goettel, Scott W. Hiebert, Sarah P. Short, Christopher S. Williams

MicroRNA-24-3p promotes skeletal muscle differentiation and regeneration by regulating HMGA1
Paromita Dey, Miles A. Soyer, Bijan K. Dey

Notch-dependent DNA cis-regulatory elements and their dose-dependent control of C. elegans stem cell self-renewal
Tina R Lynch, Mingyu Xue, Cazza W. Czerniak, ChangHwan Lee, Judith Kimble

Base editing in bovine embryos reveals a species-specific role of SOX2 in regulation of pluripotency
Lei Luo, Yan Shi, Huanan Wang, Zizengchen Wang, Yanna Dang, Shuang Li, Shaohua Wang, Kun Zhang

Transgenerational impact of aberrant inflammation in rat pregnancy
Takafumi Ushida, Tiziana Cotechini, Nicole Protopappas, Aline Atallah, Charlotte Collyer, Shannyn K. Macdonald-Goodfellow, M. Yat Tse, Louise M. Winn, Stephen C. Pang, Michael A. Adams, Maha Othman, Tomomi Kotani, Hiroaki Kajiyama, Charles H. Graham

Interchromosomal interaction of homologous Stat92E alleles regulates transcriptional switch during stem-cell differentiation
Matthew Antel, Madona Masoud, Romir Raj, Ziwei Pan, Sheng Li, Barbara G. Mellone, Mayu Inaba

Transcriptional evaluation of the ductus arteriosus at the single-cell level uncovers a requirement for vimentin for complete closure
Jocelynda Salvador, Gloria E. Hernandez, Feiyang Ma, Cyrus W. Abrahamson, Matteo Pellegrini, Robert Goldman, Karen M. Ridge, M. Luisa Iruela-Arispe

Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury
Aaron H. Wasserman, Yonatan R. Lewis-Israeli, Amanda R. Huang, McKenna D. Dooley, Allison L. Mitchell, Manigandan Venkatesan, Aitor Aguirre

Transcription factor induction of vascular blood stem cell niches in vivo
Elliott J. Hagedorn, Julie R. Perlin, Rebecca J. Freeman, Samuel J. Wattrus, Tianxiao Han, Clara Mao, Ji Wook Kim, Inés Fernández-Maestre, Madeleine L. Daily, Christopher D’Amato, Michael J. Fairchild, Raquel Riquelme, Brian Li, Dana A.V.E. Ragoonanan, Khaliun Enkhbayar, Emily L. Henault, Helen G. Wang, Shelby E. Redfield, Samantha H. Collins, Asher Lichtig, Song Yang, Yi Zhou, Balvir Kunar, Jesus Maria Gomez-Salinero, Thanh T. Dinh, Junliang Pan, Karoline Holler, Henry A. Feldman, Eugene C. Butcher, Alexander van Oudenaarden, Shahin Rafii, J. Philipp Junker, Leonard I. Zon

Impaired ability in visual-spatial attention in Chinese children with developmental dyslexia
Mengyu Tian, Runzhou Wang, Hong-Yan Bi

Chigno/CG11180 and SUMO are Chinmo-Interacting Proteins with a Role in Drosophila Testes Stem Cells
Leanna Rinehart, Wendy E. Stewart, Natalie Luffman, Matthew Wawersik, Oliver Kerscher

Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development
Ragini Phansalkar, Josephine Krieger, Mingming Zhao, Sai Saroja Kolluru, Robert C. Jones, Stephen R Quake, Irving Weissman, Daniel Bernstein, Virginia D. Winn, Gaetano D’Amato, Kristy Red-Horse

Krüppel-like factor 4 is required for development and regeneration of germline and yolk cells from somatic stem cells in planarians
Melanie Issigonis, Akshada B. Redkar, Tania Rozario, Umair W. Khan, Rosa Mejia-Sanchez, Sylvain W. Lapan, Peter W. Reddien, Phillip A. Newmark

Somatic regulation of female germ cell regeneration and development in planarians
Umair W. Khan, Phillip A. Newmark

Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells
Cai Ping Koh, Avinash Govind Bahirvani, Chelsia Qiuxia Wang, Tomomasa Yokomizo, Cherry Ee Lin Ng, Linsen Du, Vinay Tergaonkar, Dominic Chih-Cheng Voon, Hiroki Hosoi, Takashi Sonoki, Mok Meng Huang Michelle, Akiko Niibori-Nambu, Yi Zhang, Archibald S. Perkins, Zakir Hossain, Daniel G. Tenen, Yoshiaki Ito, Byrappa Venkatesh, Motomi Osato

Systematic mapping of rRNA 2’-O methylation during frog development and involvement of the methyltransferase Fibrillarin in eye and craniofacial development in Xenopus laevis
Jonathan Delhermite, Lionel Tafforeau, Sunny Sharma, Virginie Marchand, Ludivine Wacheul, Ruben Lattuca, Simon Desiderio, Yuri Motorin, Eric Bellefroid, Denis L.J. Lafontaine

Over 400 million years of cooperation: Untangling the chondrocranium-dermatocranium connection
Susan M. Motch Perrine, M. Kathleen Pitirri, Emily L. Durham, Mizuho Kawasaki, Hao Zheng, Danny Z. Chen, Kazuhiko Kawasaki, Joan T. Richtsmeier

Transient grb10a Knockdown Permanently Alters Growth, Cardiometabolic Phenotype and the Transcriptome in Danio rerio
Bridget L Evans, Terence Garner, Chiara De Leonibus, Oliver H Wearing, Holly A Shiels, Adam F L Hurlstone, Peter E Clayton, Adam Stevens

Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism
Mírian Romitti, Barbara de Faria da Fonsecaa, Gilles Doumont, Pierre Gillotay, Adrien Tourneur, Sema Elif Eski, Gaetan Van Simaeys, Laura Chomette, Helene Lasolle, Olivier Monestier, Dominika Figini Kasprzyk, Vincent Detours, Sumeet Pal Singh, Serge Goldman, Samuel Refetoff, Sabine Costagliola

HSC-independent definitive hematopoietic cells persist into adult life
Michihiro Kobayashi, Haichao Wei, Takashi Yamanashi, David J Shih, Nathalia Azevedo Portilho, Samuel Cornelius, Noemi Valiente, Chika Nishida, Wenjin J Zheng, Joonsoo Kang, Jun Seita, Jia Qian Wu, Momoko Yoshimoto

Drosophila renal stem cells enhance fitness by delayed remodeling of adult Malpighian tubules
Chenhui Wang, Allan C. Spradling

Single cell profiling of Hofbauer cells and fetal brain microglia reveals shared programs and functions
Alexis M Ceasrine, Rebecca Batorsky, Lydia L. Shook, Sezen Kislal, Evan A. Bordt, Benjamin A. Devlin, Roy H. Perlis, Donna K. Slonim, Staci D. Bilbo, Andrea G. Edlow

Stem cell specific interferon stimulated gene expression is regulated by the formative pluripotency network through IRF1
Merrit Romeike, Stephanie Spach, Marie Huber, Songjie Feng, Gintautas Vainorius, Ulrich Elling, Christa Buecker

Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes
Takumi Kitamoto, Yun-Kyoung Lee, Wendy M. McKimpson, Hitoshi Watanabe, Nishat Sultana, Wen Du, Jason Fan, Bryan Diaz, Hua V. Lin, Rudolph L. Leibel, Sandro Belvedere, Domenico Accili

A phenotypic rescue approach identifies lineage regionalization defects in a mouse model of DiGeorge syndrome
Gabriella Lania, Monica Franzese, Adachi Noritaka, Marchesa Bilio, Annalaura Russo, Erika D’Agostino, Claudia Angelini, Robert G. Kelly, Antonio Baldini

β-catenin perturbations control differentiation programs in mouse embryonic stem cells
Elisa Pedone, Mario Failli, Gennaro Gambardella, Rossella De Cegli, Antonella La Regina, Diego di Bernardo, Lucia Marucci

Circadian regulation of lung repair and regeneration
Amruta Naik, Kaitlyn Forrest, Yasmine Issah, Utham Valekunja, Akhilesh B Reddy, Elizabeth Hennessy, Thomas S. Brooks, Apoorva Babu, Mike Morley, Gregory R. Grant, Garret A. FitzGerald, Amita Sehgal, G. Scott Worthen, David B. Frank, Edward E Morrisey, Shaon Sengupta

Re-entry into mitosis and regeneration of intestinal stem cells through enteroblast dedifferentiation in Drosophila midguts
Aiguo Tian, Virginia Morejon, Sarah Kohoutek, Yi-Chun Huang, Wu-Min Deng, Jin Jiang

Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling
Muhammad Irfanur Rashid, Takuji Ito, Daisuke Shimojo, Kanae Arimoto, Kazunari Onodera, Rina Okada, Takunori Nagashima, Kazuki Yamamoto, Zohora Khatun, Hideyuki Okano, Hidetoshi Sakurai, Kazunori Shimizu, Manabu Doyu, Yohei Okada

Directing iPSC Differentiation into iTenocytes using Combined Scleraxis Overexpression and Cyclic Loading
Angela Papalamprou, Victoria Yu, Angel Chen, Tina Stefanovic, Giselle Kaneda, Khosrowdad Salehi, Chloe Castaneda, Arkadiusz Gertych, Juliane D Glaeser, Dmitriy Sheyn

The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism
Anirban Roy, Meiricris Tomaz da Silva, Raksha Bhat, Kyle R. Bohnert, Takao Iwawaki, Ashok Kumar

Single-cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells
Chen Zhang, Xueshuai Han, Jingkun Liu, Lei Chen, Ying Lei, Kunying Chen, Jia Si, Tian-yi Wang, Hui Zhou, Xiaoyun Zhao, Xiaohui Zhang, Yihua An, Yueying Li, Qian-fei Wang

| Plant development

Initiation of organ maturation and fruit ripening in grapevine is controlled by the CARPO-NAC transcription factor
Erica D’Incà, Chiara Foresti, Luis Orduña, Alessandra Amato, Elodie Vandelle, Antonio Santiago, Alessandro Botton, Stefano Cazzaniga, Edoardo Bertini, Mario Pezzotti, James Giovannoni, Julia Vrebalov, José Tomás Matus, Giovanni Battista Tornielli, Sara Zenoni

Jasmonic Acid coordinates with Light, Glucose and Auxin signalling in Regulating Branching Angle of Arabidopsis Lateral Roots
Manvi Sharma, Mohan Sharma, K Muhammed Jamsheer, Ashverya Laxmi

Dosage of duplicated and antifunctionalized homeobox proteins influences spikelet development in barley
Venkatasubbu Thirulogachandar, Geetha Govind, Götz Hensel, Sandip M. Kale, Markus Kuhlmann, Lennart Eschen-Lippold, Twan Rutten, Ravi Koppolu, Jeyaraman Rajaraman, Sudhakar Reddy Palakolanu, Christiane Seiler, Shun Sakuma, Murukarthick Jayakodi, Justin Lee, Jochen Kumlehn, Takao Komatsuda, Thorsten Schnurbusch, Nese Sreenivasulu

A vacuolar hexose transport is required for xylem development in the inflorescence stem of Arabidopsis
Emilie Aubry, Beate Hoffmann, Françoise Vilaine, Françoise Gilard, Patrick A.W. Klemens, Florence Guérard, Bertrand Gakière, H. Ekkehard Neuhaus, Catherine Bellini, Sylvie Dinant, Rozenn Le Hir

TWISTED DWARF1 regulates Arabidopsis stamen development by differential activation of ABCB-mediated auxin transport
Jie Liu, Roberta Ghelli, Maura Cardarelli, Markus Geisler

SCARECROW is deployed in distinct developmental contexts during rice and maize leaf development
Thomas. E. Hughes, Jane A. Langdale

The regeneration factors ERF114 and ERF115 act as transducers of mechanical cues to developmental pathways
Balkan Canher, Fien Lanssens, Ai Zhang, Anchal Bisht, Shamik Mazumdar, Jefri Heyman, Frauke Augstein, Sebastian Wolf, Annelie Carlsbecker, Charles W. Melnyk, Lieven De Veylder

The transcription factor AtHB23 modulates starch turnover for root development and plant survival under salinity
María Florencia Perotti, Agustín Lucas Arce, Federico Damián Ariel, Carlos María Figueroa, Raquel Lía Chan

The annotation and analysis of complex 3D plant organs using 3DCoordX
Athul Vijayan, Soeren Strauss, Rachele Tofanelli, Tejasvinee Atul Mody, Karen Lee, Miltos Tsiantis, Richard S. Smith, Kay Schneitz

CHIQUITA1 maintains temporal transition between proliferation and differentiation in Arabidopsis thaliana
Flavia Bossi, Benjamin Jin, Elena Lazarus, Heather Cartwright, Yanniv Dorone, Seung Y. Rhee

The dynamics of HD-ZIP III – ZPR protein interactions play essential roles in embryogenesis, meristem function and organ development
Anna Vitlin Gruber, Melissa Kosty, Yasaman Jami-Alahmadi, James A. Wohlschlegel, Jeff A. Long

| Evo-devo

Natural variation in the maternal and zygotic mRNA complements of the early embryo in Drosophila melanogaster
Anna A. Feitzinger, Anthony Le, Ammon Thompson, Mehnoor Haseeb, Mohan K. Murugesan, Austin M. Tang, Susan E. Lott

How to align arthropod legs
Heather S. Bruce

The Daphnia carapace and the origin of novel structures
Heather S. Bruce, Nipam H. Patel

Krüppel-like factor 4 is required for development and regeneration of germline and yolk cells from somatic stem cells in planarians
Melanie Issigonis, Akshada B. Redkar, Tania Rozario, Umair W. Khan, Rosa Mejia-Sanchez, Sylvain W. Lapan, Peter W. Reddien, Phillip A. Newmark

Cephalopod Retinal Development Shows Vertebrate-like Mechanisms of Neurogenesis
Francesca Napoli, Christina M. Daly, Stephanie Neal, Kyle J. McCulloch, Alexandra Zaloga, Alicia Liu, Kristen M. Koenig

A tripartite structure, the complex nuclear receptor element (cNRE), is a cis-regulatory module of viral origin required for atrial chamber preferential gene expression
Luana Nunes Santos, Ângela Maria da Souza Costa, Martin Nikolov, Allysson Coelho Sampaio, Frank E. Stockdale, Gang F Wangø, Hozana Andrade Castillo, Mariana Bortoletto Grizante, Stefanie Dudczig, Michelle Vasconcelos, Nadia Rosenthal, Patricia Regina Jusuf, Paulo de Oliveira, Tatiana Guimarães de Freitas Matos, William Nikovits Jr., Michael Schubert, Mirana Ramialison, José Xavier-Neto

An evolutionarily conserved cis-regulatory element of Nkx3.2 contributes to early jaw joint morphology in zebrafish
Jake Leyhr, Laura Waldmann, Beata Filipek-Górniok, Hanqing Zhang, Amin Allalou, Tatjana Haitina

Life Strategies in Placozoa
Daria Y. Romanova, Mikhail A. Nikitin, Sergey V. Shchenkov, Leonid L. Moroz

Cell Biology

A novel mechanism of bulk cytoplasmic transport by cortical dynein in Drosophila ovary
Wen Lu, Margot Lakonishok, Anna S. Serpinskaya, Vladimir I. Gelfand

Single-particle tracking of dynein identifies PP2A B55/SUR-6 as a cell cycle regulator of cortical force generation
Alan Edwards, John B. Linehan, Vincent Boudreau, Paul S. Maddox

Sequestration of LINE-1 in novel cytosolic bodies by MOV10 restricts retrotransposition
Rajika Arora, Maxime Bodak, Laura Penouty, Cindy Hackman, Constance Ciaudo

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification
Francesca M. Aloisio, Diane L. Barber

Separable mechanisms drive local and global polarity establishment in the C. elegans intestinal epithelium
Melissa A. Pickett, Maria D. Sallee, Victor F. Naturale, Deniz Akpinaroglu, Joo Lee, Kang Shen, Jessica L. Feldman

Placental structure, function and mitochondrial phenotype relate to fetal size and sex in mice
Esteban Salazar-Petres, Daniela Pereira Carvalho, Jorge Lopez-Tello, Amanda Nancy Sferruzzi-Perri

Tracheal tube fusion in Drosophila involves release of extracellular vesicles from multivesicular bodies
Carolina Camelo, Anna Körte, Thea Jacobs, Stefan Luschnig

Mouse oocytes develop in cysts with the help of nurse cells
Wanbao Niu, Allan C. Spradling

Ubiquitin ligases and a processive proteasome facilitate protein clearance during the oocyte-to-embryo transition in Caenorhabditis elegans
Caroline A. Spike, Tatsuya Tsukamoto, David Greenstein

Shaping the size of a neuronal lineage: the role of Imp and Syp RBPs in the precise elimination of neurons by apoptosis
Wenyue Guan, Mathilde Bouchet, Aurélien Darmas, Jonathan Enriquez

The sperm protein Spaca6 is essential for fertilization in zebrafish
Mirjam I. Binner, Anna Kogan, Karin Panser, Alexander Schleiffer, Victoria E. Deneke, Andrea Pauli

Tetraspanin Cd9b plays a role in fertility in zebrafish
S Greaves, KS Marsay, PN Monk, H Roehl, LJ Partridge

Pre-meiotic pairing of homologous chromosomes during Drosophila male meiosis
Thomas Rubin, Nicolas Macaisne, Ana Maria Vallés, Clara Guilleman, Isabelle Gaugué, Jean-René Huynh

CADHERIN mediated AMIS localisation
Xuan Liang, Antonia Weberling, Chun Yuan Hii, Magdalena Zernicka-Goetz, Clare E Buckley

Daughter centrioles assemble preferentially towards the nuclear envelope in Drosophila syncytial embryos
Neil H. J. Cunningham, Imène B. Bouhlel, Paul T. Conduit

Modelling

Modeling the mechanics of growing epithelia with a bilayer plate theory
Joseph Ackermann, Paul-Qiuyang Qu, Loïc LeGoff, Martine Ben Amar

Cells use molecular working memory to navigate in changing chemoattractant fields
Akhilesh Nandan, Abhishek Das, Robert Lott, Aneta Koseska

insideOutside: an accessible algorithm for classifying interior and exterior points, with applications in embryology
Stanley E. Strawbridge, Agata Kurowski, Elena Corujo-Simon, Alexander G. Fletcher, Jennifer Nichols

Scaling dictates the decoder structure
Jingxiang Shen, Feng Liu, Chao Tang

Reconstruction of dynamic regulatory networks reveals signaling-induced topology changes associated with germ layer specification
Emily Y. Su, Abby Spangler, Qin Bian, Jessica Y. Kasamoto, Patrick Cahan

Adhesion strength between cells regulate non-monotonic growth by a biomechanical feedback mechanism
Abdul N Malmi-Kakkada, Sumit Sinha, Xin Li, D. Thirumalai

Active morphogenesis of patterned epithelial shells
Diana Khoromskaia, Guillaume Salbreux

A continuum mathematical model of substrate-mediated tissue growth
Maud El-Hachem, Scott W McCue, Matthew J Simpson

Mechanochemical models for calcium waves in embryonic epithelia
Katerina Kaouri, Paul E. Méndez, Ricardo Ruiz-Baier

Global cell-cell communication enables spatial segregation of cells in organoids of the inner cell mass
Simon Schardt, Sabine C. Fischer

Interfacial friction dictates long-range force propagation in tissues
Yuting Lou, Takumi Kawaue, Ivan Yow, Yusuke Toyama, Jacques Prost, Tetsuya Hiraiwa

Reviews

Morphomics via Next-generation Electron Microscopy
Raku Son, Kenji Yamazawa, Akiko Oguchi, Mitsuo Suga, Masaru Tamura, Yasuhiro Murakawa, Satoshi Kume

Self-organization in embryonic development: myth and reality
Stuart A. Newman

From Single Cells to Flowers – Biological Complexity Driving Plant Reproductive Development
Isabel Schwarz , Manuel Neumann , Rosario Vega , Xiaocai Xu , Letizia Cornaro , Lucia Colombo, Teva Vernoux , Jian Xu , Sebastian Marquardt , Kerstin Kaufmann

Selective Drivers of Simple Multicellularity
Kai Tong , G. Ozan Bozdag , William C. Ratcliff

The Evolution of Hox Genes in Spiralia
Andreas Hejnol, Ludwik Gasiorowski , Jose-Maria Martin-Duran

Tools & Resources

MusMorph, a database of standardized mouse morphology data for morphometric meta-analyses
Jay Devine, Marta Vidal-García, Wei Liu, Amanda Neves, Lucas D. Lo Vercio, Rebecca M. Green, Heather A. Richbourg, Marta Marchini, Colton M. Unger, Audrey C. Nickle, Bethany Radford, Nathan M. Young, Paula N. Gonzalez, Robert E. Schuler, Alejandro Bugacov, Campbell Rolian, Christopher J. Percival, Trevor Williams, Lee Niswander, Anne L. Calof, Arthur D. Lander, Axel Visel, Frank R. Jirik, James M. Cheverud, Ophir Klein, Ramon Y. Birnbaum, Amy E. Merrill, Rebecca R. Ackermann, Daniel Graf, Myriam Hemberger, Wendy Dean, Nils D. Forkert, Stephen A. Murray, Henrik Westerberg, Ralph S. Marcucio, Benedikt Hallgrímsson

A toolkit to generate inducible and interconvertible Drosophila transgenes
Franz Wendler, Sangbin Park, Claire Hill, Alessia Galasso, Kathleen R. Chang, Iman Awan, Yulia Sudarikova, Mar Bustamante-Sequeiros, Sichen Liu, Ethan Sung, Gabrielle Aisabonoko, Seung K. Kim, Luis Alberto Baena-Lopez

Evaluation of CRISPR gene-editing tools in zebrafish
José M. Uribe-Salazar, Gulhan Kaya, Aadithya Sekar, KaeChandra Weyenberg, Cole Ingamells, Megan Y. Dennis

Self-organized emergence of hyaline cartilage in hiPSC-derived multi-tissue organoids
Manci Li, Juan E. Abrahante, Amanda Vegoe, Yi Wen Chai, Beth Lindborg, Ferenc Toth, Peter A. Larsen, Timothy D. O’Brien

A deep learning framework for quantitative analysis of actin microridges
Rajasekaran Bhavna, Mahendra Sonawane

Chromosome counting in the mouse zygote using low-invasive super-resolution live-cell imaging
Yu Hatano, Daisuke Mashiko, Mikiko Tokoro, Tatsuma Yao, Kazuo Yamagata

A powerful and versatile new fixation protocol for immunohistology and in situ hybridization that preserves delicate tissues in planaria
Carlos Guerrero-Hernández, Viraj Doddihal, Frederick G. Mann Jr., Alejandro Sánchez Alvarado

A method to quantitate maternal transcripts localized in sea urchin egg cortex by RT-qPCR with accurate normalization
Yulia O. Kipryushina, Mariia A. Maiorova, Konstantin V. Yakovlev

Robust temporal map of human in vitro myelopoiesis using single-cell genomics
Clara Alsinet, Maria Primo, Valentina Lorenzi, Andrew J Knights, Carmen Sancho-Serra, Jong-Eun Park, Beata S Wyspianska, David F Tough, Damiana Alvarez-Errico, Daniel J Gaffney, Roser Vento-Tormo

DeepProjection: Rapid and structure-specific projections of tissue sheets embedded in 3D microscopy stacks using deep learning
Daniel Haertter, Xiaolei Wang, Stephanie M. Fogerson, Nitya Ramkumar, Janice M. Crawford, Kenneth D. Poss, Stefano Di Talia, Daniel P. Kiehart, Christoph F. Schmidt

Paraxial mesoderm organoids model development of human somites
Christoph Budjan, Shichen Liu, Adrian Ranga, Senjuti Gayen, Olivier Pourquie, Sahand Hormoz

Single-cell Atlas Unveils Cellular Heterogeneity and Novel Markers in Human Neonatal and Adult Intervertebral Discs
Wensen Jiang, Juliane D. Glaeser, Khosrowdad Salehi, Giselle Kaneda, Pranav Mathkar, Anton Wagner, Ritchie Ho, Dmitriy Sheyn

Rapid and efficient adaptation of the dTAG system in mammalian development reveals stage specific requirements of NELF
Abderhman Abuhashem, Anna-Katerina Hadjantonakis

A single-cell transcriptome atlas of human early embryogenesis
Yichi Xu, Tengjiao Zhang, Qin Zhou, Mengzhu Hu, Yao Qi, Yifang Xue, Lihui Wang, Zhirong Bao, Weiyang Shi

Single-cell transcriptome reveals insights into the development and function of the zebrafish ovary
Yulong Liu, Michelle E. Kossack, Matthew E. McFaul, Lana Christensen, Stefan Siebert, Sydney R. Wyatt, Caramai Kamei, Samuel Horst, Nayeli Arroyo, Iain Drummond, Celina E. Juliano, Bruce W. Draper

Spatial charting of single cell transcriptomes in tissues
Runmin Wei, Siyuan He, Shanshan Bai, Emi Sei, Min Hu, Alastair Thompson, Ken Chen, Savitri Krishnamurthy, Nicholas E. Navin

The Tabula Sapiens: a multiple organ single cell transcriptomic atlas of humans
The Tabula Sapiens Consortium, Stephen R Quake

Transgenic tools for targeted chromosome rearrangements allow construction of balancer chromosomes in non-melanogaster Drosophila species
David L. Stern

When less is more – Endogenous tagging with TurboID increases the sensitivity of proximity labelling-based experiments
Alexander Stockhammer, Laila S. Benz, Christian Freund, Benno Kuropka, Francesca Bottanelli

Fast DNA-PAINT imaging using a deep neural network
Kaarjel K. Narayanasamy, Johanna V. Rahm, Siddharth Tourani, Mike Heilemann

Simultaneous multicolor DNA-PAINT without sequential fluid exchange using spectral demixing
Niclas Gimber, Sebastian Strauss, Ralf Jungmann, Jan Schmoranzer

Single organoid RNA-sequencing reveals high organoid-to-organoid variability
Kristin Gehling, Swati Parekh, Farina Schneider, Marcel Kirchner, Vangelis Kondylis, Chrysa Nikopoulou, Peter Tessarz

Stain-free Detection of Embryo Polarization using Deep Learning
Cheng Shen, Adiyant Lamba, Meng Zhu, Ray Zhang, Changhuei Yang, Magdalena Zernicka Goetz

4Dia: A tool for automated 4D microscope image alignment
Nimmy S. John, Michelle A. Urman, ChangHwan Lee

Research practice & education

Gender Imbalance in the Editorial Activities of a Researcher-led Journal
Tal Seidel Malkinson, Devin B. Terhune, Mathew Kollamkulam, Maria J. Guerreiro, Dani S. Bassett, Tamar R. Makin

Assessing Motivations and Barriers to Science Outreach within Academia: A Mixed-Methods Survey
Nicole C. Woitowich, Geoffrey C. Hunt, Lutfiyya N. Muhammed, Jeanne Garbarino

The Effect of COVID-19 on the Postdoctoral Experience: a comparison of pre-pandemic and pandemic surveys
Andréanne Morin, Britney A. Helling, Seetha Krishnan, Laurie E. Risner, Nykia D. Walker, Nancy B. Schwartz

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Mark your diaries and get your applications in for the upcoming Workshops run by The Company of Biologists.  Three Workshops that are of particular interest to developmental and stem cell biologists are currently accepting applications for funded places from early-career researchers:

• The Biology and Physics of Left-Right Patterning, 5-8 June 2022 – application deadline: 17 December 2021
• Fostering Quantitative Modelling and Experimentation in Developmental Biology, 10-13 July 2022 – application deadline: 7 January 2022
• Cell State Transitions: Approaches, Experimental Systems and Models, 24-27 July 2022 – application deadline: 21 January 2022

Want to know more about the format of our Workshops, and how and why you should apply? Our Science Communications Officer, Laura Hankins explains more here.

For a full list of 2022 Workshops, visit https://www.biologists.com/workshops/

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This project started in a somewhat roundabout way.  Our lab (the Gross lab) has focused for many years on development of the retina, lens and optic cup, eye evolution, and more recently RPE regeneration.  Several years ago, Taka Kuwajima, who is an expert in retinal ganglion cell (RGC) biology, and particularly axon regeneration, was hired into our Department.  We share lab space and have a joint weekly meeting, and had wanted to work together on a project for some time but nothing quite got started.  Then, in 2019, we had a fabulous MD/Ph.D. student, Si Chen, begin to work with us through a joint program between the University of Pittsburgh and Xiangya Hospital/Central South University in China.  Si was interested in glaucoma, so we thought about what sort of RGC-focused project we could do together that would also finally get Taka and I collaborating.

RGCs in mice die rapidly after injury.  The same is true in humans, and neither system can regenerate lost cells or axons if they are damaged.  This is what leads to the loss of vision in glaucoma – once the RGC axons comprising the optic nerve are damaged, the cells begin to die and vision progressively deteriorates.  Zebrafish have remarkable abilities to regenerate lost or damaged cells and tissues, and this is true for RGCs; when the axons of the optic nerve are damaged or even transected, zebrafish regenerate these projections and restore connections and function. Several labs are doing some really exciting work on axon regeneration including Lieve Moons, Ava Udvadia, and Dan Goldman.  While the mechanism that facilitates RGC axon regeneration is a fascinating topic, what really interested us was a slightly different facet of zebrafish RGC biology coming from earlier studies where it was reported that ~75% of zebrafish RGCs were preserved after severe optic nerve injury, even to 7-weeks post-injury (Zou et al., 2013). Again, in mammals, the RGCs die rapidly after injury and to our knowledge, no one had followed up this observation that zebrafish RGCs stayed alive after completely severing their axons. We thought this would be a great project to bring our labs together and a great in vivo system to possibly discover something new about neuroprotection.  Moreover, since there are no effective treatments to preserve RGCs in glaucoma, we thought this project might also have some exciting translational potential if we could discover genes and pathways that facilitated RGC survival after injury.

To get started, Si first repeated the experiments of Zou et al. (2013), observing exactly what they saw – RGCs did indeed survive, even after she completely severed the optic nerve!  These are tough experiments and Si has amazing skills that enabled her to develop the surgical technique and rigorously reproduce the findings.  With the model in hand, Si was then able to isolate RGCs and perform RNA-Seq to profile changes in gene expression after injury.  This is a great hypothesis-generating experiment and indeed, she identified many genes and pathways that were altered by the injury. She decided to focus on Jak/Stat signaling as a proof-of-concept that this approach could yield interesting neuroprotective factors.  Her results were striking; blocking Jak activity compromised RGC survival after injury.  What was particularly exciting was how the project then dovetailed nicely with another interest in the lab – the role of immune responses during injury and regeneration.  We had recently been studying innate immune responses during RPE regeneration (Leach et al., 2021) and leveraged some of what we had learned in that system to start to look at RGC survival. Si was able to show that blocking inflammation or depleting macrophages/microglia protected all RGCs after injury.  The Jak/Stat pathway is activated in both RGCs and macrophages/microglia after injury, so we don’t yet know if activity is required in one cell type or both, and this is something for which we’d like to develop tools to answer.

We’re excited to study some of the other genes and pathways identified in the screen and we’re also curious to see if there are more sensitive or resilient RGC subtypes.  Our research will be assisted by the beautiful single cell atlas of zebrafish RGCs recently published by the Baier lab (Kölsch et al., 2021) and work from Nick Tran and colleagues, where they have identified resilient subtypes in mouse (Tran et al., 2019). A terrific new postdoc, Ashrifa Ali, has recently joined the lab and she plans to build off of these studies, using the zebrafish model to better understand RGC survival after injury. Hopefully, this will lead to the development of new therapeutics to treat glaucoma.

In the end, this was a really fun project that brought together a fantastic MD/Ph.D. student, Si Chen, with Taka and me to work together on something new for each of us. I love this part of basic science research; we have the best jobs in the world where we can come to work every day, ask exciting open-ended questions and then figure out creative ways to answer them.  If you have a good idea and work hard, more likely than not, you will discover something new, and there aren’t many jobs that give this sort of freedom and reward.  We have a lot more to do on this project, and certainly there will be a lot of ups and downs along the way, but I’m sure it will be a fun ride.

Access the paper here: Chen, S., Lathrop, K.L., Kuwajima, T. and Gross J. M. (2022). Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between Jak/Stat signaling and innate immune responses in the zebrafish retina. Development 149 (8):dev199694

REFERENCES

Kölsch, Y., Hahn, J., Sappington, A., Stemmer, M., Fernandes, A. M., Helmbrecht, T. O., Lele, S., Butrus, S., Laurell, E., Arnold-Ammer, I., et al. (2021). Molecular classification of zebrafish retinal ganglion cells links genes to cell types to behavior. Neuron 109, 645–662.e9.

Leach, L. L., Hanovice, N. J., George, S. M., Gabriel, A. E. and Gross, J. M. (2021). The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration. Proc. Natl. Acad. Sci. U. S. A. May 25, 2021 118 (21) e2017198118.

Tran, N. M., Shekhar, K., Whitney, I. E., Jacobi, A., Benhar, I., Hong, G., Yan, W., Adiconis, X., Arnold, M. E., Lee, J. M., et al. (2019). Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes. Neuron 104, 1039–1055.e12.

Zou, S., Tian, C., Ge, S. and Hu, B. (2013). Neurogenesis of retinal ganglion cells is not essential to visual functional recovery after optic nerve injury in adult zebrafish. PLoS One 8, e57280.

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In our recently published paper¹, we show that human stem cells self-organize into blastocyst-like structures, which we term blastoids based on 4 criteria. Because blastoids can be generated in large numbers, can be finely manipulated and recapitulate aspects of endometrial implantation in vitro, they are powerful models to investigate the principles of blastocyst development and implantation. Here I want to tell the backstory of our scientific journey and why I believe it is important for science and medicine.

Nature | DOI: 10.1038/s41586-021-04267-8

Human embryology

Understanding human development is one of the new frontiers in developmental biology.  Because of the intrinsic difficulties in studying human embryos, the majority of our knowledge has been inferred from model organisms such as mice, frogs, fish, or fruit flies. However, many developmental principles are not conserved and humans have evolved specific features². Human embryos can be studied when generously donated by couples undergoing an IVF procedure, and this has proved extremely useful³. However, IVF embryos are scarce, not always of top quality, and considerably difficult to work with. On the contrary, embryo models formed from pluripotent stem cells (hPSCs), although they are simplified versions of the embryo, can be formed easily from established cell lines in the lab, generated in large numbers, and are easier to manipulate either physically or genetically. They thus represent an ethical and technical alternative complementing the use of IVF embryos.

Understanding implantation with blastoids

In our lab (Nicolas Rivron, IMBA-Institute for Molecular Biotechnology, Austrian Academy of Sciences), we are interested in understanding early mammalian development and how the embryo implants into the uterus. We are especially studying the formation of the blastocyst (day 4-7 in humans) that generates and pattern tissues to prepare the conceptus for implantation into the uterus. Implantation is the first physical contact between the mother and the embryo and an extremely crucial step towards the sustenance of the pregnancy. Implantation success marks the establishment of a clinical pregnancy as measured by levels of the hormone human chorionic gonadotropin. Of clinical importance, in humans, the steps of blastocyst development and implantation are prone to failure and are thought to account for as much as 75% of pregnancy loss^4,5.

Despite its tremendous significance, understanding blastocyst development and implantation has proven to be a challenging endeavor. This is because embryos are available in limited numbers and their interactions with the uterus happens deep inside the womb, therefore is inaccessible and invisible. These limitations in working with IVF embryos and the uterus restrain the possibilities to perform, for example, complex genetic manipulations, biochemistry, as well as high throughput chemical or genetic screens that are at the heart of scientific and biomedical discoveries. To overcome these challenges, our lab has previously developed a model of mouse blastocyst generated solely using stem cells, which we termed blastoid⁶. Mouse blastoids formed through the combination of cells from lines of mouse embryonic stem cells⁷ and mouse trophoblast stem cells⁸. When treated with a defined cocktail of growth factors and/or their modulators, these two stem cell types interact, which triggers their self-organization into structures that are remarkably similar to mouse blastocysts^6,9,10. The mouse blastoids was a first complete model of the conceptus and, because it modeled the pre-implantation stage, we were able to transfer them in utero to study implantation. No mice were formed from mouse blastoids until now but blastoids are a scalable and experimentally amenable platform to employ multimodal approaches such as complex genetic manipulations and high-throughput imaging in order to address scientific questions such as principles of embryonic/extraembryonic inductions and self-organization.

2021: Many attempts to model human blastocysts.

The mouse blastoids reported in 2018 triggered interest to form human blastoids and the potential clinical implications multiplied that enthusiasm. Till date, 6 groups independently proposed human blastocyst models, all of which were published in 2021. These 6 methods were developed using at least 4 different states of stem cells as a starting point, and 6 different culture conditions to tentatively trigger the formation of analogs of blastocyst lineages. The output with respect to the stage of the cells that were generated, the level of adequacy with developmental time and sequence, and the efficiency of the formation of structure widely varied. Overall, establishing ways of evaluating the weight of the initial experimental parameters and of defining criteria to assess the cells and structures that are formed will be essential. To our best of understanding, the initial cell state and the combination of molecules used to trigger blastoid formation are the two main parameters that, when combined, allow for modeling blastocyst development and forming the right cells reflecting the blastocyst stage.

Currently, the most powerful way to perform end-point assessments is to combine single cell RNA sequencing (scRNA seq) data of the model with a reference map generated from various staged human embryos (pre-blastocyst, blastocyst, post-implantation stages). Having multiple stages, including the ones before and after the blastocyst stage, is essential to detect potential off-target cells. Fortunately, the last few years have been fruitful in generating high-quality datasets from human embryos including IVF pre-blastocyst and blastocysts^11,12, IVF blastocysts further cultured in vitro for up to 14 days¹³, that mimic aspects of early post-implantation development. Moreover, a very recent study has created an invaluable scSeq dataset from a gastrulation human embryo (Carnegie stage 7)¹⁴. Overall, this provides an unprecedented opportunity to generate a high-quality reference meta-map from human embryos in order to evaluate embryo models. In the future, additional layers of readouts (e.g., ATAC seq, Bi-sulfite seq, etc.) would be useful to complement the analysis of the transcriptome alone.

Our own attempt to form human blastoids.

In our study¹, we report the generation of human blastoids that, to the best of our knowledge, faithfully and efficiently recapitulate key features of blastocyst development: the sequence and the pace of lineage specification and morphogenesis, which results in the formation of blastocyst-like cells. We measured 97% of blastocyst-like cells based on criterias that we think should be challenged, fine-tuned, and complemented. This reliability in modeling blastocyst development allowed us to subsequently model several aspects of implantation using endometrial organoids. Here we describe the initial cell state and combination of molecules triggering the formation of blastoids, and the end-point criteria that we think are valid to evaluate such models. the human blastocyst.

The right shade of pluripotent stem cells: a secret ingredient to faithful blastoids

In mice, the culture conditions to establish stem cell lines reflective of the blastocyst lineages are relatively well established. For example, stem cells can be captured in a state that reflects the blastocyst-stage epiblast, and that are referred to as 2i/Lif naive PSCs⁷. Similarly, the blastocyst-stage trophectoderm can be captured in a state that we refer to as trophectoderm stem cells (TESCs, unpublished manuscript)⁹. This allows these two developmentally matched stem cell types to efficiently self-organize and to form mouse blastoids. Altogether, to form a faithful and thus useful blastoid, it is crucial to begin with stem cells that reflect the blastocyst stage, and that are capable of efficiently forming and organizing analogs of the blastocyst lineages upon exposure to developmentally relevant cues.

In mice, the culture conditions to establish stem cell lines reflective of the blastocyst lineages are relatively well established. For example, stem cells can be captured in a state that reflects the blastocyst-stage epiblast, and that are referred to as 2i/Lif naive Pluripotent Stem Cells (PSCs)⁷. Similarly, the blastocyst-stage mouse trophectoderm can be captured in a constrained state that we refer to as trophectoderm stem cells (TESCs)⁹[now published in Cell Stem Cell]. This allows these two developmentally matched stem cell types to efficiently self-organize into mouse blastoids. Altogether, to form a faithful and thus useful blastoid, it is crucial to begin with stem cells that reflect the earliest stage possible, and that are capable of efficiently forming and organizing analogs of the blastocyst lineages upon exposure to developmentally relevant cues.

The human stem cells that best reflect the blastocyst stage have been difficult to capture. The firstly established and most commonly used hPSCs¹⁵ are referred to as primed hPSCs and are transcriptionally similar to the epiblast of post-implantation staged embryos (day 12-14) as compared to blastocysts (day 5-7)¹⁶. This is typically shown by measuring stage-specific molecular criteria (e.g., genome-wide DNA hypomethylation, X chromosome status^17,18) and by comparing the cells transcriptome with reference monkey¹⁹ or human datasets^11,13,14. However, in the last decade, multiple labs have shown that primed hPSCs cultured with specific signaling pathway inhibitors and activators are capable of resetting their transcriptome, decreasing the methylation of their DNA, and, to some extent, to reactivate silenced X chromosome^{17,18,20–22}. These shades of naive pluripotency reflect the blastocyst epiblast (~ day 6). Other attempts to reset primed hPSCs allowed to capture other states, for example human extended potential stem cells (hEPSCs)²³ but, upon re-analysis, these cells display a transcriptome more similar to the post-implantation stage (see analysis in Figure 7²⁴ and Figure 3²⁵).

The unrestricted potential of naive human pluripotent stem cells

The mouse and human blastocysts comprise 3 lineages: the trophectoderm that mediates implantation and then generates the placenta, the epiblast that forms the majority of the body, and the primitive endoderm that forms the yolk sac and part of the embryonic endoderm. In mice, the specification of the trophectoderm occurs during the transition from a morula to a blastocyst²⁶. On the contrary, studies by the laboratories of Laurent David (INSERM and Université de Nantes, France) and Hilde van de Velde (Vrij Universiteit Brussel) have suggested that the early human blastocyst doesn’t comprise fully specified cells but rather cells that are not yet entirely restricted to a specific lineage^{12 27}. In correlation with this observation, the laboratories of Yasuhiro Takashima (CiRA) and of Austin Smith (Exeter University) have shown that naive hPSCs cultured in either PXGL²⁰ or Ti2iLGö¹⁸ are capable of forming analogs of the blastocyst-stage trophectoderm^28,29. Once again, this potential is in sharp contrast to the already determined potential of mouse PSCs that cannot efficiently form trophoblasts, as assessed in chimeric and in vitro assays^30–32. Of note, although several studies have described the potential of primed hPSCs or hEPSCs to differentiate into cells with trophoblast-like properties, this process does not seem efficient, and the obtained cellular populations might be heterogeneous and reflecting a mix of post-implantation trophoblasts and amnion cells (a lineage thought to emerge during the post-implantation period) rather than the trophectoderm (that forms in the blastocysts). However, these attempts to efficiently form trophoblasts from primed hPSCs were very successful in order to learn about the signaling pathways^33,34 regulating aspects of trophoblast specification and pinpointing the important plasticity of human cells as compared to mouse cells.

The right signalling activity combination- TGF-β, ERK and Hippo inhibition: other secret ingredient

Therefore, considering the similarities of naive PXGL hPSCs to the blastocyst epiblast and the enhanced plasticity of human cells as compared to mice, we tested the potential of PXGL hPSCs to form human blastocyst-like structures. To do so, we formed a small aggregate of cells (~80-100 um) and provided molecules that were previously found to support either the formation of human trophoblasts (inhibition of TGF-β with A83-01³³, ERK with PD03^28,29,33,35) or to participate in the maintenance of mouse TESCs (inhibition of Hippo pathways with LPA⁹), and to maintain naive hPSCs (LIF)²¹, along with a ROCK inhibitor to enhance cell survival and aggregation. To our surprise, within 96 hours, this culture condition was sufficient to induce the very efficient self-organization of the aggregates into structures that bear remarkable morphological resemblance to the human blastocyst. This protocol is robust and, with minor tuning of concentration of inhibitors, multiple hPSC,both ESC and iPSC, lines formed such structures with remarkably high efficiency (70-90% for every cell line we tested).

Fantastic 4 features: Rise of the human blastoids

For embryo models to be valuable, they must possess a good level of analogy with the embryo. Therefore, here we benchmarked our blastocyst-like structures using several known features of the human blastocyst. Here, we propose 4 cardinal features that define a human blastoid.

1.  Size, morphology, and cell numbers: A fully expanded human blastocyst consists of a trophectoderm cyst of diameter between 150-250 μm that surrounds a single fluid-filled cavity and encompasses a single cluster of inner cells. We used the threshold of 150-250um diameter to define a blastoid and thus their yield of formation. These blastoids showed remarkable morphological resemblance to the human blastocysts and surprisingly, almost always form only one inner cell cluster of Inner Cell Mass (ICM)-like cells. Moreover, the total number of cells as well as ratios between various compartments are conserved as well (Figure 1h¹). However, in order to better benchmark blastocyst-like structures, a more detailed and more extensive reference dataset of cell numbers within each lineages and over blastocyst development time (e.g., day 4-7), would be highly valuable.

2.  Timing and sequence of development: The human blastocyst forms towards the end of the 4th day after fertilization and continues to develop for the next 3 to 4 days, at which time (~days 7-8) it undergoes implantation. Thus, blastocyst development from its formation to implantation takes 3 to 4 days. During that time, a precise sequence of events happens: First, the trophectoderm and ICM form. Then, in a second step, the ICM generates GATA4+ primitive endoderm cells and the trophectoderm matures to form NR2F2+ polar trophectoderm.  This developmental dynamics of lineage specification was spontaneously recapitulated during blastoid formation: Similar to human blastocysts, trophectoderm and ICM analogs were the first lineages to form (24-60 hours), while primitive endoderm and polar trophectoderm analogs only formed in the second stage (60-96 hours). Of note, analogs of primitive endoderm and of the polar trophectoderm formed autonomously, solely based on the initial conditions, and probably due to intrinsic cell interactions and positional information originating from the overall geometry of the structures. No external stimulations are necessary during intermediate stages.. This pace matching is important in order to ultimately form cells that reflect the blastocyst stage. The necessity to culture cells for a longer time in order for morphogenesis to occur properly would also lead to the formation of cells reflecting the post-implantation rather than pre-implantation stage.

3.  Transcriptomic states and stage: Human blastocysts ultimately consist of only three cell types, epiblast, trophectoderm and primitive endoderm that are each characterized by a distinct transcriptome. Importantly, these transcriptomes significantly differ from that of their derivatives in the post-implantation stages. It is thus possible to qualitatively infer the stage equivalent of the cells based on their transcriptome. However, methods to put hard numbers on this remain insufficiently developed. It is crucial for blastoids to be composed of analogs of only the blastocyst cell types and devoid of their post-implantation derivatives or of any other ‘off-target’ cell types. Several recent studies have reported high quality single cell transcriptomic datasets from human embryos of various stages ranging from morula to gastrula^11,13,14. The latest one was produced by the laboratory of Laurent David (INSERM and Université de Nantes, France) who combined a metadataset and developed a pseudotime trajectory that appeared extremely useful³⁶. An efficient and relaxed collaboration with this laboratory allowed us to have precise reference maps in order to determine the stage of the cells formed within the blastocyst-like structures and the precise cell states composing them. Ultimately, the blastocyst-like structures formed contained only three main, transcriptionally distinct clusters and each individual cluster showed a gene signature of epiblast, trophectoderm and primitive endoderm respectively. However, the decisive experiment came when we projected these cells on the human embryonic reference map consisting of cells isolated from pre-blastocyst, blastocyst, in vitro cultured blastocyst (equivalent of day 7 to day 14), and gastrulating embryos (CS7). The cells isolated from the blastocyst-like structures coincided quite precisely with the transcriptome of the cells of the blastocyst but not with pre-blastocyst stages or any post-implantation stages. Specifically, the transcriptome of the cells that formed overtime matched with day 5 blastocysts after 24 hours, and with day 7 blastocysts after 96 hours thus revealing the stages that are modeled. We found a minor population of ‘off-target’ cells which accounted for less than 3% of the cells analyzed. Thus, with morphological resemblance to human blastocyst, efficient formation of analogs of blastocyst cells according to the sequence and pace of blastocyst, and absence of off-target cells, we now felt confident to refer to these structures as blastoids.

4.  Implantation and post-implantation developmental potential: Between day 4 and day 7 after fertilization, the blastocyst forms a cavity, which expands. During this, the blastocyst prepares itself to interact with the uterus so as to implant in the right direction and facilitate subsequent embryonic development. For example, the trophectoderm patterns into 2 distinct zones: the trophectoderm cells closer to the epiblast form the polar trophectoderm while the cells on the opposite end form the mural trophectoderm. In human blastocysts, such patterning is key for implantation as the polar trophectoderm forms the sticky cells that mediate the initial interactions with the endometrial cells of the uterus. Strikingly the trophectoderm analogs of the majority of blastoids (>60%) were patterned into polar and mural-like trophectoderm cells as seen by their protein expression profile (NR2F2High/CDX2Low). This indicated that the blastoids may possess the ability to undergo directional implantation. However, it is of course unethical and now forbidden by the ISSCR to transfer human blastoids into the uterus of humans or any other model organisms for any purpose including for scientific experiments^37,38.

Therefore, we developed, through a fruitful and fun collaboration with Nina Maenhoudt and Hugo Vankelekom (KU Leuven, Belgium), an in vitro implantation assay using the cells from the endometrial organoids. We were extremely fascinated to see that, when blastoids were deposited on endometrial cells previously stimulated with hormones, blastoids attached to the endometrial cells thus mimicking the first step of implantation. However, this interaction did not occur if endoTherefore, we developed, through a fruitful and fun collaboration with Nina Maenhoudt and Hugo Vankelekom (KU Leuven, Belgium), an in vitro implantation assay using the cells from the endometrial organoids. We were extremely fascinated to see that, when blastoids were deposited on endometrial cells previously stimulated with hormones, they attached to the endometrial cells thus mimicking the first step of implantation. However, this interaction did not occur if endometrial cells were not stimulated with hormones. In accordance with clinical knowledge, we concluded that the hormones changed the state of the endometrial cells and made them receptive for the blastoid. Even more surprisingly, upon live imaging, we realized that this initial interaction was reproducibly mediated by the cells on the polar side of the trophectoderm. This was an exciting moment for us because replicating this directional attachment to hormonally stimulated endometrial cells gives confidence that we can mimic important aspects of the initiation of implantation. Importantly, the exposure of blastoids to a STAT inhibitor (SC144) and to a strong Hippo inhibitor (XMU-MP01) prevented the formation/maintenance of the inner cell cluster and thus to the formation of trophospheres. These trophospheres that transcriptionally appear to most resemble mid-stage blastocysts were incapable of attaching to hormonally stimulated endometrial cells. These additional controls reinforced our conviction that this assay demonstrated the specificity and reliability of blastoids to mimic aspects of implantation. It also opens up new possibilities to understand the molecular basis of embryo-uterus cross talk during implantation. Finally, blastoids can also be cultured for an extended period of time after their attachment to endometrial cells, during which they consistently expand and attain several features of post-implantation human embryos. For example, some trophectoderm cells differentiate into syncytiotrophoblast and extravillous trophoblast; the epiblast begins to express CD24 and appear more epithelial. However, since the methods to culture human blastocysts to post implantation stages are currently suboptimal, the extended blastoid cultures cannot be appropriately benchmarked. We do not think that we have properly modeled a day 13 stage. Nevertheless, blastoids cultured to extended periods augurs well for using these to study peri-implantation embryonic development.

The above criteria canThe above criteria can be used to determine the reliability and predictive power of any in vitro blastocyst model. We propose that these initial criteria must be thoroughly evaluated in order to define the in vitro structures as blastoids. However, we also acknowledge that these criteria are currently minimal. With further research more features such as the proteomic and epigenetic status, the mechanisms of lineage specification, the X chromosome status, etc., must be benchmarked to the human blastocysts and such features measured to evaluate the quality and utility of the model.

Publishing human blastoids: A long roller coaster ride

The journey between the generation of the first human blastoid in our lab to the first submission of our manuscript was an intense one. Several members of the team took responsibility for different aspects of the study and worked in a highly coordinated manner. Though intense, the team made this journey an exciting and delightful one. We submitted our manuscript with a completely optimized blastoid to the journal Nature on the 12^th of February 2021. At that time, no other protocol to form models of the human blastocyst had been published. The editor received our manuscript with a lot of enthusiasm but there was definitely a shared sense of urgency to publish it. As a consequence, the first round of the peer review process was accelerated as well. We are extremely thankful to our reviewers Jan Bronsens, Jianping Fu, Insoo Hyun (open reviewers) and 2 other anonymous reviewers for the fast yet mostly constructive criticisms and the suggested experiments. However, the editor gave us a hard deadline of only 4 months to revise the manuscript and only one chance for re-submitting a manuscript that would address all the reviewer’s comments.

This brought back the intense phase, but this time with a deadline. Our synergistic work and the help of Maria Novatchkova (an excellent bioinformatician at the Vienna Biocenter) and collaborators, especially in that revision phase, from the lab of Laurent David, made it possible to submit a revised manuscript after approximately 3 months, about one month before the deadline. However, during this phase several reports were published reporting blastocyst-like structures, albeit with low efficiency. Though we were disappointed, we were rejoiced by the interest that the scientific community has towards this field.

Within weeks after the first attempts were released, a consortium of independent stem cell biologists and embryologists led by Fredrik Lanner (Karolinska Institute) and Sophie Petropoulos (Montreal University) gathered to evaluate the state and the stage of the cells within these models. They used an extensive reference map formed by parametrizing and merging multiple datasets of cells harvested a pre-blastocyst, blastocyst, and post-implantation stages. The initial report from this consortium was very rapidly published on Biorxiv and reported the abundance of ‘non-blastocyst’ like cells that closely resemble several post-implantation cell types present in the amnion, mesoderm, and primitive streak (~day 14)³⁹. The presence of such ‘off-target’ cells is probably due to the sub-optimal initial cell state and/or suboptimal combination of molecules, which results in slow development (6 days or 9 days) and in a process of directed differentiation that led to the formation of cells similar to the gastrulation (day 14) and germ layer (mesoderm) stages. We suspect this, along with the low efficiency,  can greatly reduce the utility of the model. It reignited our enthusiasm to finalize our proposition to form a model of human blastocyst-stage embryo.

While setting up rapid and good standards for the field, this independent consortium report probably caused an unprecedented scrutiny over our manuscript. We received very positive comments from 2 out of 3 of the reviewers which hinted our optimistic minds towards the acceptance of our manuscript. In the meantime, an ethicist, who turned out to be Insoo Hyun (open reviewer no. 4) gave us an ethical green light based on compliance with ISSCR guidelines and on the assessed oversight by the Austrian Academy of Sciences. However, the editor decided to add an additional reviewer (Reviewer no. 5) specifically to ensure the validity of the generation and analysis of the single cell transcriptomic data used to claim the formation of cells reflecting the blastocyst stage. Although disappointed by that unexpected move that consumed more time than we anticipated, we were excited to learn a bit more than one month later, at the end of August, that our scRNA seq analyses had passed this additional test. In addition, an update of the meta-analysis led by Fredrik Lanner and Sophie Petropoulos also included our model along with the one formed in the lab of Ge Guo (Exeter University) and showed that these models reflect the blastocyst stage. Forming the right cells is crucial because only faithful embryo models will be capable of reliably predicting human development. This will ensure that we can trustfully use embryo models to infer the (epi)genetic mechanisms, molecular pathways and cellular behaviors of blastocysts. While this first report from the consortium is important, more detailed analysis (such as quantitative assessment of the resemblance of a specific cell type of a blastocyst model to the one of the blastocyst) would be extremely beneficial to assess degrees of similarity. Such an understanding of the initial cell state and of the combination of molecules that allow for the formation of human blastoids also call for unbiased re-analysis of single cell RNA sequencing (scSeq) by independent bioinformaticians. It would support valid scientific and medical discoveries, and assist ethical evaluations.

The editor then sent us a ‘provisional’ acceptance (provided it clears the editorial criteria) on September 3rd, 2021. However, for reasons that we do not understand, we had to anxiously wait for more than 75 days for our manuscript to become formally accepted on the 18th of November, 2021. Finally, the study was published on the 2nd of December 2021, 3 months after provisional acceptance, through an accelerated track gladly proposed by the editor.

We hope that the scientific community has read our study with as much excitement as we had when first realizing that these blastoids form reliably according to the cardinal features of human blastocysts (size/morphology/cell numbers, timing/sequence of development, transcriptomic states/stage, functional implantation, and post-implantation developmental potential). Our data points to the possibility that the proposed blastoid is valuable to study early human development. Overall, this scientific journey shows that the initial cell state (PXGL naïve hPSCs) and the combination of molecules (triple inhibition of the Hippo/ERK/TGF-β pathways) allow for the formation of human blastoids that accurately form blastocyst-stage cells. However, we strongly encourage independent groups and bioinformaticians to critically work with our sequencing data sets to compare with that of human embryos to verify or challenge our analysis. Afterall, self-correction can only allow for the field to progress toward more stringent criteria and models predictive of human blastocyst development and implantation.

Blastoid team: great companions in a gratifying journey

Working on the project to develop human blastoids was a rare opportunity that I was extremely privileged to experience. I am extremely thankful to my supervisor Nicolas Rivron for providing me this opportunity. The most striking aspect to me was his broad vision behind the development of the project and the tremendous planning to execute the ideas in a highly coordinated manner. This was made possible by the extremely supportive and helpful atmosphere in the lab. When I started working in this lab, in January 2020, I joined the efforts of an extremely talented postdoc, Harunobu Kagawa, in characterizing naive PSCs and human trophoblast stem cells. Meanwhile, in parallel, another postdoc, Heider Hedari Khoei, who joined the lab just 2 days after me, used his clinical expertise on endometrial organoids.  Through collaborative work with Nina Maenhoudt and Hugo Vankelekom (KU Leuven, Belgium), he developed the in vitro implantation assay. Thus, when we successfully developed our first human blastoid, we had already established a system to assess their functionality by the implantation assay. This synergistic team work within the lab (Theresa Sommer and Yvonne Scholte Op Reimer performed  several crucial experiments and Giovanni Sestini led all the analysis of all the sequencing data) as well as collaborations (Labs of Laurent David, Hugo Vankelekom and Thomas Freour) allowed for the realization of this exciting study. This has been a learning experience and a journey that I will cherish. Blastoids have now opened up a new opportunity to dive deep into exploring mechanisms underlying early embryogenesis in humans. Thus, the exciting journey continues.

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Doing great science depends on teamwork, whether this is within the lab or in collaboration with other labs. However, sometimes the resources that support our work can be overlooked. In our new series, ‘Featured Resource’, we aim to shine a light on these unsung heroes of the science world. For our second article, we interviewed Kevin Thiessen, the person behind the twitter account @ZebrafishRock. Read on to find out more about Kevin, the information he shares on @ZebrafishRock, and how it can help your scientific career. To conclude our post, we borrow some feedback collected by Joaquín Navajas Acedo (aka @MadS100tist) to support his nomination of Kevin for the SDB ‘Trainee Science Communication Award’.

Kevin, please could you start by introducing yourself and tell us about your scientific background and your current research.

I’ve been in research labs for the last twelve years with diverse topics that have ranged from pancreatic cancer in mice, to innate immunity of avian species, to inner ear development in fish. I worked as a technician after my undergraduate studies before going to graduate school at Creighton University School of Medicine in Omaha, Nebraska, USA. I earned my PhD in Biomedical Sciences in 2019. Then, I was in Germany for a couple years doing a postdoctoral fellowship at Ulm University, where I researched heart development and regeneration. Currently, I am a Research Associate at the University of Bristol, UK, working with Dr Beck Richardson and the Scar Free Foundation to uncover genes that are involved with scarring and wound healing. Zebrafish are an optimal research organism as they utilise scar free healing of wounds such as the heart and skin. As part of the Scar Free mission, we hope to activate or supress these processes in humans to achieve a world without scarring.

Why (and when) did you start ‘Zebrafish Rock!’?

I originally started the account in 2016, during graduate school, to share my enthusiasm about zebrafish as I was active in a lot of community outreach using this model. On Twitter, I would act like a personified zebrafish and interact with others on the platform. It was largely anonymous and mischievous, but at the same time I would highlight everything related to zebrafish on the feed. It became quite popular with over a thousand followers. Unfortunately, I couldn’t maintain the account as my mental health suffered in graduate school near the end of 2016, so I decided to close the account the following year. Once I was in a better place mentally, I reopened the account in 2018 with the goal of establishing Zebrafish Rock! as a central feed for all things zebrafish. The anonymity was now gone, which did wonders for my mental health. The revamped coverage removes the nonsense and focuses on the news, research, and jobs. Now, the account has nearly seven thousand followers and I think that’s attributed to the new consistent coverage.

What information do you aim to share?

I really try to highlight anything that is new and exciting in the field. I’m not very selective in what the account promotes. If I haven’t seen it before, it usually gets a retweet. I especially love when first authors (who are usually graduate students and Postdocs) share a thread about their new research papers. Also, I’ve started to cover other teleost models such as cavefish and killifish to connect them with the zebrafish community.

Which are your favourite posts to write?

It takes a lot of my spare time on Sunday mornings, but I enjoy writing the #DanioDigest. It covers everything from community news to recent papers/preprints and job postings. I enjoy it because it gives me time to educate myself on the latest research and I believe it benefits others that may not have as much time to sort through the whole feed. I try to post it every two weeks, if my schedule allows it.

What is your favourite hashtag and what are the top hashtags to look out for?

My favourite hashtag must be #GuessThatISH. The zebrafish community is really lucky to have an outstanding resource such as the zebrafish model organism database, ZFIN. One of their best features is the carefully curated and extensive list of in situ expression images by Thisse and Thisse et al. I use these images to play a fun guessing game with the community. The answers can be hilarious during the ‘Wrong Answers Only’ edition.

The most popular hashtag has been #AskZebrafish, where people ask questions to the online community. If I know someone that might have an answer or can help, I usually ping them in the replies. It creates great discussions. The hashtag has been successful with people finding transgenic fish stocks, reagents, and helpful advice. Other popular hashtags include #ZebrafishJobs (where people post open positions) and #ZebrafishZunday (where I share images and videos of zebrafish with credit on Sundays).

Do you have any new features planned for ‘Zebrafish Rock!’?

I constantly have new ideas for features and I often lose track of the ones I have done in the past. There are a few I want to bring back such as #ZebrafishFunFacts (as the name implies, this is interesting fun facts about zebrafish) and #TeleostTalk (focussing on different teleost models used in biomedical research). A new feature I’m working on is #KnowYourZDM, where I highlight zebrafish research models of human disease.

What can the community do to help?

The community has really embraced the account and I’m really thankful for that. They can continue to tell their colleagues and labmates about the benefits of using Twitter.

‘User’ feedback

Recently Joaquín Navajas Acedo aka MadScientist asked the zebrafish community for feedback on Zebrafish Rock! so he could nominate Kevin for the SDB ‘Trainee Science Communication Award’. Click on the tweet below to read the replies he received, and scroll down the post to see a few of his favourites.

Dear #devbio Community and #zebrafish tweeps: I am nominating @kdthiessen for the @___SDB___ 'Trainee Science Communication Award'. Could please reply or DM me letting me know how this account has helped your research or learning something new about zf? Thanks! RT appreciated https://t.co/x2GqXG3NF6

— MadScientist (@MadS100tist) October 27, 2021

Below are some of Joaquín’s favourites:

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Welcome to our light-hearted look at the goings-on in the world of developmental biology in the last two weeks (or so).

Talking points on Twitter

• The latest craze on twitter is to post artwork using your paper title or job title as a prompt, created using the AI illustrator app https://app.wombo.art/. See our artwork using the Node strapline and ‘Vibrant’ art style below!

• Single-cell analysis still under discussion;

pic.twitter.com/M6IS1WHSTA

— MadScientist (@MadS100tist) November 23, 2021

• and with a festive theme

My mind – “Single cells…” 😂😂 pic.twitter.com/U7ohpBfpCT

— Suhrid Ghosh (@ghoshnotgosh) November 28, 2021

Single cells, single cells
UMAP all the way,
Batch correction, what a ride,
What, then imputation? hey!

Single cells, single cells
Zeros all the way,
I guess you really need to hide
Behind shoddy PCA https://t.co/rI7BCLjY6Z

— Adam MacLean (@adamlmaclean) November 29, 2021

• It’s nice to be nice!

The science points to fact that *receiving* gratitude has significant positive effects on our mental and physical health. (This is very different than making gratitude lists of things we are thankful for.) The takeaway: Thank others & recall other people’s genuine thanks of you.

— Andrew D. Huberman, Ph.D. (@hubermanlab) November 23, 2021

• Looking for inspiration, there are so many great questions here:

Friends, I’d love to know what open questions you’re stoked about (esp. if you think a non-traditional organism or unique biology in a traditional one holds the key). Would concerted effort/tech advancement unlock? Want to know that too. Reply here & I may ping you to learn more!

— Prachee Avasthi (@PracheeAC) November 30, 2021

Gene editing news in the News

In the UK, the government is considering proposals to allow gene editing in commercial livestock. The report emphasised the importance of putting animal welfare first.

https://www.bbc.co.uk/news/science-environment-59480907

Three days later, a paper from James Turner, Peter Ellis and colleagues explained how gene editing could spare animal suffering by producing single-sex litters

https://www.bbc.co.uk/news/science-environment-59505112

Prelights in #Devbio

A comprehensive 3D+t atlas of heart tube formation and looping

Thanks to the #DevBio community for making this such an interesting couple of weeks, especially on twitter. If you have some news that you think we should share with the developmental biology community on our blog, please get in touch at thenode@biologists.com. If you are interested in getting involved with writing preLights you can find out more here.

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In the latest Genetics Unzipped podcast, Kat Arney chats with Professor Paige Harden from the University of Texas about her new book, The Genetic Lottery, exploring how genetic variations might affect our chances in life, and what – if anything – we should do with this information.

Harden argues that variations in our DNA that make us different, in terms of our personalities and our health, can affect our chances of educational and economic success in life. Rather than ignoring these differences, or simply saying “well, if it’s genetic, what can you do about it?”, she puts forward some ideas for how we can use our knowledge about genetics to achieve more equitable outcomes for everyone.

Genetics Unzipped is the podcast from The Genetics Society. Full transcript, links and references available online at GeneticsUnzipped.com.

Subscribe from Apple podcasts, Spotify, or wherever you get your podcasts.

Head over to GeneticsUnzipped.com to catch up on our extensive back catalogue.

If you enjoy the show, please do rate and review on Apple podcasts and help to spread the word on social media. And you can always send feedback and suggestions for future episodes and guests to podcast@geneticsunzipped.com Follow us on Twitter – @geneticsunzip

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2021 has been an exciting year for both FocalPlane and the Node; both sites have new Community Managers, new series and new contributors. To celebrate the end of the year and to look forward into 2022, we bring you our Countdown to 2022. Each day we will feature an image from a scientist or illustrator that has contributed to our sites over the past year. We would like to thank all the participants for contributing to the calendar, particularly those that made original artwork/compositions.

We hope you enjoy viewing the calendar as much as we enjoyed making it!

Best wishes,

Esperanza and Helen

You can view the calendar here, and see daily update on our twitter, Instagram and Facebook

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My glimpse into systems biology

I was introduced to the ideas of systems biology during my first year of Natural Sciences at Cambridge University. The interplay between modelling and data collection was very appealing to me. Thanks to one of my supervisors – Tim Fulton (also a PhD student in the Steventon Lab, University of Cambridge)- I was exposed to it in the context of developmental biology. He helped me get in touch with Dr Berta Verd whose interdisciplinary approach to research enticed me. We talked a lot and came up together with my project. Due to Covid we had to modify it to include modelling, but I found it more rewarding that way!

Studying bipotent posterior progenitors in Cichlids

I researched Neuromesodermal progenitor cells (NMps). They are a very interesting population of cells, persisting beyond gastrulation to generate both mesodermal and neural fates in the late embryo. This progenitor state is characterised by coexpression of two transcription factors – Brachyury (Tbxta) and Sox2 (Henrique et al. 2015). There are inter-specific differences in their proliferation dynamics – in chick and mouse embryos they proliferate, but in zebrafish they do not (Steventon and Martinez Arias 2017). This suggests they might be tuneable during the evolution of different axial elongation patterns (Sambasivan and Steventon 2021). My project was part of a larger effort in the Verd lab to see whether this might explain axial diversity observed in Lake Malawi cichlids.

I studied the NMps in Astatotilapia calliptera and Rhamphochromis chillingali – two species of cichlids from the Lake Malawi flock. They underwent a recent radial adaptation around a million years ago. Remarkably, the genetic differences between these species are very small (between 0.1-0.25% inter-specific divergence), while the morphological differences are immense (Malinsky et al. 2018). In particular, the vertebral count differs between those 2 species, making them a very suitable experimental system for studying the evolution of axial elongation.

I did in situ hybridisations of the fish embryos at various stages, with the help of Shannon Taylor – a PhD student in the Verd Lab. We used Hybridisation Chain Reaction v3.0 (Choi et al. 2018). Despite our best efforts we did not manage to get Sox2 to work in the tailbud. This meant I could not quantify NMps as one of the crucial markers was missing. This was a very humbling experience – experimental biology is much more capricious than I had thought. However, it also showed me what cooperation between labs can look like. Tim did a lot of HCR staining in zebrafish at the Steventon lab in Cambridge and so we asked him for advice. It turned out it took them a few months to get Sox2 working! This was very reassuring. Tim gave us some tips, but we only managed to try some of them. Figure 1. contains some of the best images we obtained.

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Modelling axial elongation

In parallel to the experimental work, I investigated the effect of blebbistatin – a myosin II inhibitor – on somitogenesis and axial elongation in zebrafish. In collaboration with the Steventon lab I analysed almost 100 timelapses of zebrafish embryos in order to determine if the rate of somitogenesis is influenced by blebbistatin. My analysis showed that it is not changed (Figure 2.). Other experiments with dye injection and cell tracking from the Steventon lab showed that the tail still elongates, but with limited cell mixing. This got us curious, how is that possible?

In order to help address that problem I developed a conceptual model of the zebrafish Presomitic Mesoderm (PSM) elongation. I approximated the PSM as a uniform tissue in the form of a cut-off cone. To recreate the convergence-extension mechanism responsible for axial elongation in the zebrafish tail (Thomson et al 2021; Tada and Heisenberg 2012) I gave the cells two rules for movement: they have to stay a certain range of distances apart from each other, keeping the tissues continuous and preventing cells from occupying the same space; and the cells converge towards the x-axis, mimicking the convergence movements. I found that certain combinations of parameter values indeed lead to elongation without extensive mixing, which shows that – in agreement with our experimental observations – mixing itself seems to not be required for elongation but might rather be a side effect of a certain mode of elongation (Figure 3.).

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Summary

This was my first time being fully immersed in the lab. I actively took part in the lab meetings and journal clubs which were just as edifying as research itself! Overall, this was an incredible experience. It showed me that experimental biology is unpredictable and the relationship between results and time invested is non-linear. In contrast, computational biology has a much more linear relationship, almost always yielding something interesting! It also gives you the space to learn and think about underlying biological processes, how to recreate them in silico, consolidating your knowledge. This probably furthered my understanding of development the most! I am adamant I want to incorporate both experimental and computational approaches in my future research. I also gained much more understanding and appreciation of developmental biology and I want to specialise in it. I want to thank Berta, Tim, Shannon, Charlotte, Georgina, James, and Callum for welcoming me into their lab and helping me with the project, as well as BSDB for funding it.

References

Choi, Harry M.T., Maayan Schwarzkopf, Mark E. Fornace, Aneesh Acharya, Georgios Artavanis, Johannes Stegmaier, Alexandre Cunha, and Niles A. Pierce. 2018. “Third-Generation in Situ Hybridization Chain Reaction: Multiplexed, Quantitative, Sensitive, Versatile, Robust.” Development (Cambridge) 145 (12). https://doi.org/10.1242/dev.165753.

Henrique, Domingos, Elsa Abranches, Laure Verrier, and Kate G. Storey. 2015. “Neuromesodermal Progenitors and the Making of the Spinal Cord.” Development (Cambridge) 142 (17): 2864–75. https://doi.org/10.1242/dev.119768.

Malinsky, Milan, Hannes Svardal, Alexandra M. Tyers, Eric A. Miska, Martin J. Genner, George F. Turner, and Richard Durbin. 2018. “Whole-Genome Sequences of Malawi Cichlids Reveal Multiple Radiations Interconnected by Gene Flow.” Nature Ecology and Evolution 2 (12): 1940–55. https://doi.org/10.1038/s41559-018-0717-x.

Sambasivan, Ramkumar, and Benjamin Steventon. 2021. “Neuromesodermal Progenitors: A Basis for Robust Axial Patterning in Development and Evolution.” Frontiers in Cell and Developmental Biology. Frontiers Media S.A. https://doi.org/10.3389/fcell.2020.607516.

Steventon, Ben, and Alfonso Martinez Arias. 2017. “Evo-Engineering and the Cellular and Molecular Origins of the Vertebrate Spinal Cord.” Developmental Biology 432 (1): 3–13. https://doi.org/10.1016/J.YDBIO.2017.01.021.

Tada, Masazumi, and Carl-Philipp Heisenberg. 2012. “Convergent Extension: Using Collective Cell Migration and Cell Intercalation to Shape Embryos.” Development 139 (21): 3897–3904. https://doi.org/10.1242/DEV.073007.

Thomson, Lewis, Leila Muresan, and Benjamin Steventon. 2021. “The Zebrafish Presomitic Mesoderm Elongates through Compression-Extension.” BioRxiv, March, 2021.03.11.434927. https://doi.org/10.1101/2021.03.11.434927.

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The IBDM is an internationally renowned research center in developmental biology that studies fundamental mechanisms governing the organization and function of biological systems, using multiscale approaches in a range of animal and cellular models. Research activities at the IBDM synergistically connect developmental biology with molecular, cell and computational biology, as well as evolution, neurobiology, physiology, physiopathology, biophysics, and cancer. The IBDM uniquely fosters interdisciplinary approaches by its intimate connections with various research-training networks within the Aix-Marseille University (AMU) (CenTuri, NeuroMarseille, ICI (Cancer-Immuno), MarMaRa (Rare-Diseases), Marseille Imaging, Canceropôle-PACA).

The IBDM, affiliated with CNRS and AMU, strongly benefits from its collaborative and international scientific culture, English working language, and its fantastic environment on the Marseille Luminy campus, located in the heart of the Calanques National Park.

The IBDM is committed to promoting equality, diversity and inclusivity. The selected candidates will receive support to establish a group in a fully renovated building, have access to cutting-edge scientific core facilities,and will be assisted in obtaining a tenured position (CNRS or AMU), and in securing extramural funding (ATIP/Avenir, ERC, etc…).

To apply

• Candidates should provide the following information in a single PDF file: a cover letter explaining their motivation to join the IBDM, a CV, a summary of their main research achievements (2 pages maximum), a future research project (5 pages maximum), and contacts of three references.
• Applications and queries should be sent to the search committee (ibdm-call2022@univ-amu.fr) before March 1st 2022.
• In person interviews will be scheduled from May 2022.

Contact

ibdm-call2022@univ-amu.fr

Annoucement in pdf

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