The Institut de Génomique Fonctionnelle de Lyon (IGFL) has an opening for a new independent group leader. The IGFL has a unique scientific profile and fosters an outstanding international environment. Teams address basic research questions at the interfaces of evolution, physiology and development using functional genomics, bioinformatics, genetics and comparative approaches. The IGFL has a strong focus on integrative, organism-level research using a diversity of model and non-model organisms.
More information at: https://www.nature.com/naturejobs/science/jobs/636517-research-group-leader-opening
You can find our recently published eLife paper here.
At the Euro-Evo-Devo meeting in Lisbao I saw a talk by Sylvie Rétaux and became hooked by a blind and unpigmented cavefish: the evo-devo model Astyanax mexicanus. I then had the chance to join Sylvie’s group in Gif-sur-Yvette (France) in 2013, for a post-doc. Four years later we come out with this paper of which I’m extremely happy, not least because this study owes a great deal to teamwork and wouldn’t have been possible without a fantastic collaborative spirit between enthusiast and passionate team members. Because the “author contribution” section didn’t quite capture my feeling about the human adventure behind our paper, I’d like to take this blog post as a platform to properly acknowledge each of my friends and bring to you our scientific/team-story.
Astyanax mexicanus, evo-devo top model
Astyanax mexicanus is a teleost fish that inhabits South American rivers. As well as the river dwelling fish, several Astyanax populations can be found deep in the caves of the Sierra del Abra in Mexico. Cave colonization has occurred several times independently and these cave populations have experienced convergent evolution of several traits, including loss of eyes and pigmentation. Cave fish also behave differently than their surface siblings, probably in response to selective forces driving adaptation to life in complete and permanent darkness. For instance, they have a better sense of smell and more appetite, they swim more and sleep less, almost constantly exploring their environment in the quest for food or sexual partner. Astyanax is a great model to link developmental evolution with adaptation to a new environment. By comparing the anterior brain of surface and cave fish, and by doing so in young embryos, Sylvie’s team have been highlighting how development of the central nervous system has shaped cavefish evolution.
Our recently published work makes a new contribution to the story of Astyanax brain evo-devo. And for the first time we were able to elucidate some links between early embryonic development and fish behavior. To reach this goal, it tooks 4 years, 3 co-first authors (me-Alexandre Alié, Jorge Torres-Paz and Lucie Devos), the contribution of two brilliant students (Lise Prunier and Fanny Boulet), the unwavering support of our lab manager (Maryline Blin) and the expertise of our specialist in behavioral studies (Yannick Elipot).
From early development…
The story began before I joined the group, with the work of Lise. At that time she was a Master’s degree student and had performed very numerous and beautiful in situ hybridization showing more NPY neurons in cavefish brain versus more Pomcb neurons in surface fish brain. When Lise had to leave the lab at the end of her internship, Sylvie offered me to dig deeper into this story. Together with Maryline, I started to characterize the expression of 9 neuropeptides, at 4 embryonic stages in the 2 morphotypes (cave versus surface)… 72 different conditions in total, reproduced several times to get statistics. This could have been frustrating at some point, but few weeks after I started Lucie joined our lab for her master internship. Lucie galvanized us with her contagious enthusiasm! Our hours spent at the microscope to count/recount neurons or to debate the anatomical interpretations of our results became so much more fun by our combined efforts.
On our way to observe Astyanax cavefish in their natural environment. In the depths of the caves too, mutual support helps to follow the right path.
We next embarked on a series of double fluorescent ish to establish a co-expression map between Lhx genes and neuropeptides. Again, help was at hand from a skillful student, Fanny, who did a fantastic job with these double FISH (no pun intended), under the ever-watchful eye of Maryline. We have the chance to possess a fancy confocal microscope in the lab, and we were so excited to get into the very intimacy of Astyanax brain. The expression domains and dynamics of Lhx7 and Lhx9 strongly suggested a role for these genes in the formation of NPY-positive and Hcrt-positive (two neuropeptides) neurons, respectively. This has been definitely confirmed thanks to Jorge, a new postdoc who joined the group and took over the project when I left the lab for other horizons. Jorge’s rigorous injections of morpholinos and RNAs and his repeated cell counts again clearly established the functional links between the Lhx transcription factors and the corresponding neuropeptides. Sylvie was so happy, her favorite transcription factor Lhx9 she had discovered in the mouse 20 years ago, was involved in the process of developmental evolution of her favorite animal, the cavefish!
In parallel, we tested the role of Fgf and Shh signaling, pathways well-known to play a role in cavefish brain evolution and eye loss. For these pharmacological experiments, the fact that Astyanax produces hundreds of eggs every morning made this task easier. But what was even better was the chance to work with a cohesive and efficient team to collect, sort and dechorionate the eggs, then to treat them, wash them, fix them, even when it involved working in the middle of the night, for several nights in a row. All the authors of this paper contributed to these pharmacological experiments!
… to behavior evolution
After we had established the link between early signaling, early expression of Lhx genes and differences in neuropeptidergic neuron numbers, Sylvie next encouraged us to complete the story by linking these differences to adaptive behavior observed in cavefish. Honestly, I was not very keen on going down this road, which I thought could be long and difficult. And I was right indeed… it was so hard to get there, especially for Jorge, who worked the most on this and probably suffered a bit. With the behavioral set-up being in a distant building, I think that he had to walk dozens of kilometers to, ironically, demonstrate that the Lhx9-dependant increased number of Hcrt neurons is responsible of hyper locomotion in cavefish. However with the help and the expertise of Yannick, who achieved a level of excellence in behavioral studies on Astyanax, and Cynthia, the engineer responsible for the platform of fish behavior analysis in the Department, problems were solved and we got nice results.
And here we were! We finally got our story, linking the evolution of embryonic development, to neuro-anatomy and behavior. And we got it as a team! Brought together by the trust of Sylvie, and by mutual confidence and friendship: who could ask for more from a postdoctoral experience? I am also very grateful for the opportunity to have contributed to several other papers during this post-doc. Lucie and Jorge are also conducting their own research projects, which will surely benefit from the team spirit in a group where everybody is willing to help the others, and more importantly where everybody feels free to ask for help. As Claude Bernard says: “The idea is the seed; the method is the soil which enables it to develop…” and I believe that teamwork is the best fertilizer helping to yield the best fruits.
This summer, the Company of Biologists, the not-for-profit publisher of Development, is running a Workshop on ‘Development and evolution of the human neocortex‘, organised by Victor Borrell, Wieland Huttner and Arnold Kriegstein.
The Company of Biologists Workshops provide leading experts and early career scientists from a diverse range of scientific backgrounds with a stimulating environment for the cross-fertilisation of interdisciplinary ideas. The programmes are carefully developed and are intended to champion the novel techniques and innovations that will underpin important scientific advances.
There are currently multiple funded spaces for early-career researchers to attend this exciting event (deadline = 23 March). To find out more and apply online please visit
On 2016-5-18, the second day after my first research paper 1 was published online at my third year of PhD courses, my mentor Rongwen Xi told me to take over the “EEP project”. This project had begun long before I started my PhD courses, and until my participation, has been passed along by three researchers in turn: Na Xu, Pin Huang, and Chenhui Wang; each of them subsequently graduated and moved on with their own academic or industrial paths. Encouraged by my first successful publication, I quickly agreed to take this seemingly never-ending project. I told Dr. Xi a sentence that amused me afterwards, “I won’t give it up until you give up.” This is how this long and tough process begins, and this is also the instant that determines the end of the story.
Introduction
Even as adults, we have stem cells throughout our bodies that are responsible for maintaining many of our tissues. These adult stem cells constantly divide and produce daughter cells, which, through a process called differentiation, become multiple types of mature cells. The fate of the daughter cells can be actively specified by asymmetric cell division, in which cell fate determinants are specifically segregated into one of two stem cell daughter cells 2. Alternatively, cell fate can be specified passively; in this case, cells physically depart from the self-renewal niche environment, as with the specification of cystoblasts from Drosophila germline stem cells, and the initiation of differentiation of stem cells in the mouse small intestine upon their departure from the Paneth cell niche 3,4. Despite several implications from these “renew or differentiate” fate determination events, very little is known about the molecular mechanisms by which distinct, lineage-restricted progenitor cells are generated from a common stem cell pool.
To study this question, we investigated cell fate in a multipotent intestinal stem cell (ISC) experimental model from adult fruit flies. The default mode for cell fate is that ISCs differentiate into enterocytes (EC), which have been shown to occur from approximately 90% of ISC divisions 5. However, there is a less-well-understood mode in which ISCs differentiate into pairs of enteroendocrine cells (EEs), which occur from approximately 10% of ISC divisions.
When I started to do this project, previous studies suggested that EEs are directly differentiated from ISCs, implying that the decision of EE specification may occur at the stem cell level in ISCs 6,7, but how this occurs remains unclear. It has also been revealed that the four-gene cluster acheate-scute complex (As-c) act as EE-fate-determination factors. Furthermore, one of the As-c genes, scute (sc), is both necessary and sufficient for EE specification. Nevertheless, important questions remain about both the molecular and cellular mechanisms through which Sc functions in EE fate decision, and we do not yet know how Sc is regulated in ISCs to control EE fate.
We finally answered these questions in our recent paper, in which we reported that transient activation of Sc determines both the type and number of committed progenitor cells from Drosophila ISCs.
Figure 1. A graphic model to describe how ECs and EEs are respectively generated from ISCs. Notch-signaling-guided EC generation from ISCs acts as the default mode, while transient expression of Sc triggers EE generation from ISCs. Oscillatory expression of Sc in ISCs is achieved by transcriptional self-stimulation combined with a negative feedback regulation between Sc and E(spl) proteins & other Notch targets. During the generation of EEs, increased Sc expression induces asymmetric cell division that generates a new ISC and an EEP; residual Sc activity in the newly formed EEP is then able to induce one round of cell division and precisely generate a pair of EEs.
A cell fate is determined by a transiently expressed protein
To better understand the process of EE specification in ISCs, we set up an EE regeneration assay and examined de novo EE regeneration. This assay was first beautifully set up by Na Xu and Pin Huang. Based on the finding that Sc is required for EE generation from ISCs, we temporally knocked down sc starting from the pupal stage, and this process produced flies with midguts lacking EE cells. We then used these EE-less midguts to examine the process of EE production by using temperature shift to re-introduce Sc expression in the midgut. With this assay, we discovered that (i) ISCs actually undergo an initial division to generate a new EE progenitor cell (EEP), and (ii) the EEP then undergoes one final round of cell division to produce a pair of EEs (Figure 2).
Figure 2. An EE-regeneration model reveals that ISCs self-renew during the generation of EE pairs. (a-b) Patterns of ISC (marked by anti-Dl, red on membrane) and EE cells (marked by anti-Pros, red in nuclear) during sc-RNAi mediated EE depletion (a) and the following EE regeneration (b). An ISC undergoes self-renewal before generating an EEP, and 71% of EEPs undergoes one round of mitosis to generate a pair of EEs, and the rest directly differentiate into a single EE.
To further analyze this two-step cell division process, Chenhui Wang genetically overexpressed sc in ISCs and monitored the cellular events in a time-course experiment. Chenhui found that transient sc expression caused a rapid cell division response, and also induced expression of the EE-marker gene Pros, which is known as a potent cell-cycle inhibitor. These findings and subsequent experiments enable us to precisely define the regulatory circuitry that directs the formation of a pair of EEs from each ISC (Figure 1). Here a concern still exists that we have not given a “seeing is believing” results for cellular events of EE generation because we have not established long-term live imaging technique for fly midgut yet. To solve this problem, I expressed a UAS-RedStinger reporter in sc overexpression system. RedStinger is relatively stable and can serve as a lineage marker to trace the progeny of the originally marked ISCs. The number of cell divisions of the initially labeled ISCs could be deduced based on the mitotic marker PH3 and the number of RedStinger+ cells in a single cluster. In this experiment, I observed a tightly ordered process: The first cell division following sc overexpression occurred in ISCs (PH3+ in a one-cell clone), and at telophase of the first cell division, one of the two daughter cells began to show cytoplasmic Pros accumulation; the second cell division (PH3+ in a two-cell clone) always occurred in the Pros+ daughter cell, that is EEP; the third cell division (PH3+ in a three-cell clone) occurred again in ISCs. These observations suggest that EEs are generated from ISCs via two rounds of cell divisions: an asymmetric division of ISC to generate an EEP, and then the EEP division to produce an EE pair (Figure 3).
Figure 3. The process of sc-overexpression-induced EE generation from ISCs. (a-e) Expression of Dl>RedStinger (red), PH3 (green) and Pros (white) during sc-overexpression-induced mitosis. Sc induction in ISCs promotes asymmetric cell division that generates EEPs, which begin to show punctate nuclear Pros expression. Each EEP immediately divide once prior to terminal differentiation, yielding a pair of EEs.
Next, to visualize the expression of Sc in midgut, Pin generated a green fluorescent protein (GFP) tagged line for Sc in collaboration with Zhongsheng Yu and Renjie Jiao from the Institute of Biophysics of the Chinese Academy of Sciences. In this line, the GFP was fused to 3’ of the Sc coding region. Initially we were a little bit disappointed as the GFP signal was too weak to visualize and all the researchers had to immunostain with anti-GFP antibody, which effectively amplified the Sc-GFP signal. Immunostaining results revealed that Sc-GFP could be observed in virtually all ISCs but the expression level is largely indistinguishable among ISCs. With improved microscopy technology, I managed to capture GFP signal in unstained samples and found that the Sc-GFP fusion protein is expressed at higher levels in ~15% of the ISCs (Figure 4). This result was exciting because it indicated that Sc may be expressed in a dynamic manner in ISCs, and in a snap shot, you may see a weak expression level in most ISCs, and increased expression levels in a small subset of ISCs.
Figure 4. Sc is expressed in a small subset of ISCs. (a) A diagram showing genomic information for C-terminal insertion of EGFP in sc gene region. (b-c) Expression of Sc-GFP (green), Dl (white) and Pros (red) in midgut of 5-7 day old flies.
The next step was to test the cell lineage fate of these Schigh ISCs. The follow-up cell lineage tracing studies with a Sc-Gal4 line will help to do that, but there was no available Sc-Gal4 line at that time. Fortunately, from 23 (upstream and downstream) glass multiple reporter (GMR) enhancer-GAL4 lines generated for sc, I identified one GAL4 line that drove UAS-GFP expression in some diploid cells in the midgut epithelium. The density (also in ~15% ISCs), distribution, and individual variability of the GFP+ cells were largely similar to those of Sc-GFP+ cells, and about half of RFP reporter driven by this GAL4 line recapitulates Sc-GFP expression, suggesting that this GAL4 line is driven by the enhancer element for sc expression in the midgut. Cell lineage tracing studies with this GAL4 line revealed that the immediate daughter cells of Sc-GAL4+ ISCs were mainly EEs; however, these ISCs re-assume their default EC-producing fate once Sc expression is downregulated (Figures 1&5).
Figure 5. The cell lineage tracing results with the Sc-Gal4 line.
The knotty problem
With these exciting new observations, we inevitably faced a mechanistic question, “How does such transient upregulation of Sc in ISCs occur?” This question comes like a boss in video games, and has always been difficult to tackle. Studies over the decades on proneural genes have revealed that the AS-C genes in the neural cell lineages are regulated by highly-complex-cis-regulatory regions, and these regulatory regions are considered to constitute an integrating device for multiple signaling regulators and chromatin factors. Firstly came to our minds was to avoid such “net” and to set out from the reported signals that regulate EE specification in Drosophila midgut. Previous studies suggest that the Slit molecules secreted from EEs activate the Robo2 receptors of ISCs to prevent EE generation, thereby establishing a negative feedback to coordinate EE production with tissue demand. However, Sc expression pattern was unaltered in Robo2 mutants, in which the excessive EE phenotype was prominent. Considering Robo2 activation in ISCs is not sufficient to prevent EE production from ISCs, this mechanism appears to be a modulator rather than a key component in the EE fate decision process. Thus, I had to go back to hit the core of the question, the transcriptional control of As-c genes.
Previous studies on early Drosophila development have suggested reciprocal regulatory relationships between AS-C genes and the enhancer of split complex (E(spl)) genes, which are known as the Notch target genes. Inspired by these reports, I screened a number of candidate reporters for individual E(spl) genes, and identified a single reporter, m8-lacZ, which showed a weak, but similar expression pattern to Sc in wild type guts. To characterize the regulatory relationship between Sc and E(spl)m8, I transiently overexpressed sc in ISCs, and surprisingly saw robust upregulation of m8-lacZ expression in all ISCs. Notably, co-expressing Notch-RNAi did not prevent the upregulation of m8-lacZ expression caused by sc overexpression, suggesting that E(spl)m8 expression is independent of Notch activity in ISCs. To test whether such regulatory relationship similarly applies to other E(spl) genes, I sorted out sc-overexpressed ISCs for mRNA profiling by RNA-seq analysis. Strikingly, in addition to m8, many other E(spl) genes, including m4, m6, m7, mγ, and mδ were strongly upregulated upon sc overexpression. By combining genetic assays and ChIP-seq analysis, we showed Sc could bind to the enhancer regions of many E(spl) genes, and directly upregulate these E(spl) genes in ISCs (Figure 6).
It’s then instinctive to consider whether these E(spl) genes, also known as neural fate repressors, would in turn negatively regulate Sc expression. By combining genetic assays and targeted DamID analysis using a E(spl)m8-Dam fusion line, we showed that E(spl)m8 suppresses sc expression by directly binding to the enhancer region of sc. The direct two-way regulation between Sc and E(spl)m8 form a typical negative feedback regulatory loop, which may explain the transient activation pattern of Sc in ISCs (Figure 6).
The question still has half part unanswered, “how does sc initially build up?” Searching for other transcriptional activators, like other bHLH activators as reported, would make this question a “chick and egg” issue. Interestingly, Sc has been reported to transcriptionally self-stimulate itself, which acts as an essential mechanism for proneural protein accumulation during sensory organ development. To test whether self-stimulation of Sc also occurs in ISCs, we constructed LacZ transcriptional reporter for sc using the Sc-Gal4 enhancer fragment that we had identified. This lacZ reporter was barely detectable in WT midgut epithelium, but effectively induced in ISCs when sc was transiently induced. ChIP-seq data analysis also revealed two Sc binding peaks within this Sc-Gal4 enhancer region (Figure 6). Thus, Sc is able to stimulate its own transcription directly by binding to sc enhancer. Together, our results suggest that two feedback regulatory loops control the transient upregulation of Sc in ISCs prior to EE fate commitment. There is a transcriptional self-stimulation loop that allows Sc to gradually build up and eventually reach a high level to induce EEP specification, and there is a negative feedback regulation loop between Sc and E(spl) genes that returns sc expression back to the baseline level (Figure 1).
Figure 6. Regulatory feedback loops control Sc expression in ISCs. (a-b) Overexpression of m8 rapidly reduced sc-GFP and Dl expression in all ISCs. (c-d) GMR14C12-lacZ (LacZ reporter for Sc-Gal4 line) was nearly undectable in normal midgut epithelium. Overexpression of sc in ISCs led to GMR14C12-lacZ expression in progenitor cells and newly formed EEs. (e) DamID analysis for E(spl)m8 and ChIPseq analysis for Sc in ISCs revealed binding activities for both E(spl)m8 and Sc at the GMR14C12 region.
The beginning of the end
Given that negative feedback is a common mechanism underlying biochemical oscillations in virtually all organisms, the feedback loops between Sc and E(spl) genes could plausibly be the driver of an oscillatory expression pattern for Sc in ISCs; in theory such oscillatory expression could potentially serve as an internal timer for periodic production of EEs from ISCs. This clock mechanism would be similar to what is known about the circadian clocks, a biological research field that was recently honored with the 2017 Nobel Prize for Physiology or Medicine. We are obviously very excited about the findings and potential implications. However, this is just a tip of iceberg, future cellular and molecular analysis, likely in combination with in vivo live imaging work will allow further testing and refining of the oscillation model proposed in our study, and such experiments will determined whether and how any internal timer is regulated by certain endogenous and/or environmental cues, and whether the oscillation model is generally applicable in other tissue stem cells, including that in humans.
Finally, I want to say that I am very fortunate and grateful to be a part of such a wonderful research team and work on such an exciting project. This work would not be possible without the contribution and help from our past and current lab members, especially Na Xu, Chenhui Wang, and Pin Huang, as well as informaticians Huanwei Huang and Tao Cai at NIBS. I especially want to thank my mentor Dr. Xi for his great guidance and trust, as well as his helpful advice on the writing of this article. As you can imagine, in addition to the “high” moments when the exciting results were first observed, I also had many upset and head-scratching moments during the course of this study. These experiences have endowed me a lot on how to explore, to observe, to cooperate, to write, and to persevere. I believe that no matter how hard it seems like, if you continue to stay focused and think hard, great things may eventually happen, in an instant.
A few days back over dinner at a CNV gathering, Theresia Gutmann from the Coskun lab casually told me about her PhD work. In collaboration with the Rockefeller University NYC, Theresia had visualized the changing conformation of the human insulin receptor upon insulin binding (paper). I made a sketchnote summarizing their discovery of a conformational switch that could explain how the insulin receptor transforms information about extracellular ligand binding into an intracellular activity to react by taking up glucose!
A postdoc position is available in the Lehoczky Lab (Brigham and Women’s Hospital/Harvard Medical School). The lab is focused on understanding the molecular basis of mouse digit tip regeneration, with the ultimate goal of teasing apart the genetic pathways necessary for this process. For more information about the lab see LehoczkyLab.org
Applicants with a strong background in regenerative biology, genetics, developmental biology, and/or molecular biology are encouraged to apply. Prior experience with mouse genetics is preferred. Experience with RNAseq analysis is a plus.
Interested candidates should provide: 1) cv, 2) a brief letter detailing your interest in the lab and relevant past research experience, and 3) contact information for three references who can comment on your research
Application materials and any questions regarding the position should be sent to Jessica: jlehoczky@bwh.harvard.edu
Our latest monthly trawl for developmental biology (and other cool) preprints. Let us know if we missed anything.
On February 20th, The Company of Biologists launched preLights, a community-led preprint highlighting service. A panel of early career researchers (the ‘preLighters’) select and comment on recent preprints that caught their eye, and encourage preprint authors to answer any questions about the work that they had. So far it looks great, and the developmental biology content has been especially good (see the dedicated subjectcategory). We’d love to know what you think: you can contact the team via the site or the Twitter feed.
The idea behind the site was influenced in part by this list – as it got longer and longer (reflecting increased preprint usage), we were wondering how else we could encourage and promote the discussion of preprints, and the preLights idea took form. Rest assured that this list will live on, at least until the point at which it gets impossibly long!
And here’s the list – all the developmental biology I could find, plus relevant and cool other preprints thrown in for good measure.
The preprints were hosted on bioRxiv, PeerJ, andarXiv. Use these links to get to the section you want:
Axial progenitors after 8 days of differentiation, from Frith, et al.’s preprint
Human axial progenitors generate trunk neural crest cells. Thomas J.R. Frith, Ilaria Granata, Erin Stout, Matthew Wind, Oliver Thompson, Katrin Neumann, Dylan Stavish, Paul R Heath, James O.S. Hackland, Konstantinos Anastassiadis, Mina Gouti, James Briscoe, Valerie Wilson, Mario R Guarracino, Peter W Andrews, Anestis Tsakiridis
Zebrafish embryogenesis from Hess, et al.’s preprint
A conserved regulatory program drives emergence of the lateral plate mesoderm. Christopher Hess, Karin Dorien Prummel, Susan Nieuwenhuize, Hugo Parker, Katherine W. Rogers, Iryna Kozmikova, Claudia Racioppi, Sibylle Burger, Eline C. Brombacher, Alexa Burger, Anastasia Felker, Elena Chiavacci, Gopi Shah, Jan Huisken, Zbynek Kozmik, Lionel Christiaen, Patrick Mueller, Marianne Bronner, Robb Krumlauf, Christian Mosimann
Hedgehog signaling controls progenitor differentiation timing during heart development. Megan Rowton, Andrew D. Hoffmann, Jeffrey D. Steimle, Xinan Holly Yang, Alexander Guzzetta, Sonja Lazarevic, Chul Kim, Nikita Deng, Emery Lu, Jessica Jacobs-Li, Shuhan Yu, Erika Hanson, Carlos Perez-Cervantes, Sunny Sun-Kin Chan, Kohta Ikegami, Daniel J. Garry, Michael Kyba, Ivan P. Moskowitz
Neutralizing Gatad2a-Chd4-Mbd3 Axis within the NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency. Nofar Mor, Yoach Rais, Shani Peles, Daoud Sheban, Alejandro Aguilera-Castrejon, Asaf Zviran, Dalia Elinger, Sergey Viukov, Shay Geula, Vladislav Krupalnik, Mirie Zerbib, Elad Chomsky, Lior Lasman, Tom Shani, Jonathan Bayerl, Ohad Gafni, Suhair Hanna, Jason Buenrostro, Tzachi Hagai, Hagit Masika, Yehudit Bergman, William J. Greenleaf, Miguel A. Esteban, Yishai Levin, Rada Massarwa, Yifat Merbl, Noa Novershtern, Jacob H. Hanna
Adaptive Reduction of Male Gamete Number in a Selfing Species. Takashi Tsuchimatsu, Hiroyuki Kakui, Misako Yamazaki, Cindy Marona, Hiroki Tsutsui, Afif Hedhly, Dazhe Meng, Yutaka Sato, Thomas Stadler, Ueli Grossniklaus, Masahiro M. Kanaoka, Michael Lenhard, Magnus Nordborg, Kentaro K. Shimizu
Firefly genomes illuminate parallel origins of bioluminescence in beetles. Timothy R Fallon, Sarah E Lower, Ching-Ho Chang, Manabu Bessho-Uehara, Gavin J Martin, Adam J Bewick, Megan Behringer, Humberto J Debat, Isaac Wong, John C Day, Anton Suvorov, Christian J Silva, Kathrin F Stanger-Hall, David W Hall, Robert J. Schmitz, David R Nelson, Sara Lewis, Shuji Shigenobu, Seth M Bybee, Amanda M Larracuente, Yuichi Oba, Jing-Ke Weng
10 Aquilegia species species from Filiaut, et al.’s preprint
The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water. David Armisen, Rajendhran Rajakumar, Markus Friedrich, Joshua B Benoit, Hugh M Robertson, Kristen A Panfilio, Seung-Joon Ahn, Monica F Poelchau, Hsu Chao, Huyen Dinh, HarshaVardhan Doddapaneni, Shannon Dugan-Perez, Richard A Gibbs, Daniel ST Hughes, Yi Han, Sandra L Lee, Shwetha C Murali, Donna M Muzny, Jiaxin Qu, Kim C Worley, Monica Munoz-Torres, Ehab Abouheif, Francois Bonneton, Travis Chen, Li-Mei Chiang, Christopher P. Childers, Andrew G Cridge, Antonin JJ Crumiere, Amelie Decaras, Elise M Didion, Elizabeth Duncan, Elena N Elpidina, Marie-Julie Fave, Cedric Finet, Chris GC Jacobs, Alys Jarvela, Emily J Jennings, Jeffery W Jones, Maryna P Lesoway, Mackenzie Lovegrove, Alexander Martynov, Brenda Oppert, Angelica Lilico-Ouachour, Arjuna Rajakumar, Peter N Refki, Andrew J Rosendale, Maria Emilia Santos, William Toubiana, Maurijn van der Zee, Iris M Vargas Jentzsch, Aidamalia Vargas Lowman, Severine Viala, Stephen Richards, Abderrahman Khila
In vivo CRISPR-Cas gene editing with no detectable genome-wide off-target mutations. Pinar Akcakaya, Maggie L. Bobbin, Jimmy A. Guo, Jose Malagon Lopez, M. Kendell Clement, Sara P. Garcia, Mick D. Fellows, Michelle J. Porritt, Mike A. Firth, Alba Carreras, Tania Baccega, Frank Seeliger, Mikael Bjursell, Shengdar Q. Tsai, Nhu T. Nguyen, Roberto Nitsch, Lorenz Mayr, Luca Pinello, Mohammad Bohlooly-Y, Martin J. Aryee, Marcello Maresca, J. Keith Joung
Multiple laboratory mouse reference genomes define strain specific haplotypes and novel functional loci. Jingtao Lilue, Anthony G Doran, Ian T Fiddes, Monica Abrudan, Joel Armstrong, Ruth Bennett, William Chow, Joanna Collins, Anne Czechanski, Petr Danecek, Mark Diekhans, Dirk-Dominic Dolle, Matt Dunn, Richard Durbin, Dent Earl, Anne Ferguson-Smith, Paul Flicek, Jonathan Flint, Adam Frankish, Beiyuan Fu, Mark Gerstein, James Gilbert, Leo Goodstadt, Jennifer Harrow, Kerstin Howe, Mikhail Kolmogorov, Stefanie Koenig, Chris Lelliott, Jane Loveland, Richard Mott, Paul Muir, Fabio Navarro, Duncan Odom, Naomi Park, Sarah Pelan, Son K Phan, Michael Quail, Laura Reinholdt, Lars Romoth, Lesley Shirley, Cristina Sisu, Marcela Sjoberg-Herrera, Mario Stanke, Charles Steward, Mark Thomas, Glen Threadgold, David Thybert, James Torrance, Kim Wong, Jonathan Wood, Fengtang Yang, David J Adams, Benedict Paten, Thomas M Keane
Reproducible big data science: A case study in continuous FAIRness. Ravi K Madduri, Kyle Chard, Mike D’Arcy, Segun C Jung, Alexis Rodriguez, Dinanath Sulakhe, Eric W Deutsch, Cory Funk, Ben Heavner, Matthew Richards, Paul Shannon, Ivo Dinov, Gustavo Glusman, Nathan Price, John D Van Horn, Carl Kesselman, Arthur W Toga, Ian Foster
A NIH-funded postdoctoral position is available as early as April 1st in the laboratory of Katherine Fantauzzo in the Department of Craniofacial Biology at the University of Colorado Anschutz Medical Campus to study the in vivo dynamics of PDGFR dimer-specific formation and the resulting effects on gene expression and cell activity during mouse craniofacial development. This project will utilize an array of complementary approaches such as bimolecular fluorescence complementation, mass spectrometry and conditional mutagenesis in the mouse embryo, with the ultimate goal of providing therapeutic directions aimed at the treatment of human birth defects such as cleft lip and palate. We are seeking highly motivated, creative and interactive applicants with the ability to work independently. Preference will be given to applicants with a strong background in biochemistry and/or mouse developmental biology who published a first-author paper as a result of their Ph.D. work. More information about our group and research interests can be found on our laboratory website (http://www.fantauzzolab.org). Interested candidates should apply through the CU careers website (https://cu.taleo.net/careersection/2/jobdetail.ftl?job=12799&lang=en) with a letter of interest, a curriculum vitae and contact information for three professional references.
How do cells give rise to the functional architecture of the brain? This is no longer a neuroscience-only question. Indeed, it is a cellular, genetic, developmental, mechanical, and material problem that requires experts from all of these disciplines working together to understand how the brain works! Yet, from this architectural design perspective, it is very hard to unite the leaders in these distinct fields of research to find an answer to this complex problem. Excitingly, this was exactly what happened at the Company of Biologists workshop entitled “Thinking beyond the dish: taking in vitro neural differentiation to the next level” organized by Madeline Lancaster and Denis Jabaudon. As some of the early-career researchers invited to participate, we each provide our perspectives on this amazing workshop and we are extremely grateful to the organizers and the Company of Biologists for putting this together.
GUILLERMO GOMEZ Group Leader, Centre for Cancer Biology, SA Pathology and the University of South Australia
Being myself a mechano-biologist, I was very excited about the brain organoids developed by Madeline Lancaster and Jürgen Knoblich and I became more curious on what would be next, what is the future of this technology, something that seems is becoming closer to science fiction. This was the key layout for this meeting: Thinking “beyond” the dish…., which by far exceeded my expectations.
The meeting was small but excellent. We had great talks on how we can create different types of materials to manipulate almost all class of its properties, and now, more excitingly, doing it precisely in space and time, to control cell behavior. We had also geneticists who show how single cell transcriptomics allows the creation of “expression trees” that link all the different cells that form these minibrains and described the genetic network architectures that contribute to the robustness of brain development in the early mammalian embryo (so everyone looks similar during gestation) but which then diversifies when we become more mature (so everyone looks different later). It was also really exciting how using this technology now it is possible to establish neural circuits based on organoids and also how these could contribute, for example, to the restoration of brain tissue to improve recovery in brain cancer patients after the resection of the tumor.
But where do we go now? We discussed it a lot through this meeting and my feeling is that we are still far from being able to integrate all these aspects because of its complexity and some limitations of the approach, to be able to make entire brains in the dish. But we are seeing the light on this technology to understand in a more physiologically relevant setting the fundamentals of the brain architecture and how is it affected in different type of diseases, for which strong interdisciplinary interactions are crucial. This meeting has seeded the grounds to be able to do it and gave me the chance to meet the leaders in these interdisciplinary areas, which has really fueled me with ideas and new perspectives about this problem. This is exactly what I needed at this very early stage of my independent career.
CRISTIANA CRUCEANU Postdoctoral Fellow, Max Planck Institute of Psychiatry, Munich, Germany.
I first became aware of the Company for Biologists workshops at the recommendation of one of my mentors, who suggested I would really enjoy the topic – and the format. She was right. If selected, I could have one of 10 coveted early-career scientist spots, and join 20 senior thought leaders in my field to learn about the latest research, discuss future directions, and potentially build collaborations. So I put in an application for the workshop entitled “Thinking beyond the dish: taking in vitro neural differentiation to the next level”, and got to attend from 4 – 7 February 2018. For a psychiatric geneticist looking to update our available in vitro model systems for the human brain using organoids, this seemed just perfect.
I was quite thrilled to test my research and ideas with a topically diverse audience, yet intimately focused on one important topic. How can cerebral organoids, one of the most promising developments of recent years, achieve the status of ‘workhorse of neuroscience’? I credit the organizers, Denis Jabaudon and Madeline Lancaster, for bringing together an eclectic group of scientists and engineers who covered the spectrum from neurodevelopment to bioengineering to psychiatry. The talks were wonderful for laying out the complex problem ahead, and the strides currently being made toward addressing it. The venue – a historical stately manor named Wiston house cradled between rolling green hills occupied by sheep (even in February!) – provided the perfect familiarity to foster discussion and exchange of ideas that would lead to collaborations worthy of speeding up discovery and innovation.
After 4 days of intense learning, exquisite meals, and stimulating discussions over drinks, I left inspired and motivated. I feel confident that cerebral organoids will be exponentially improved in the coming years, leading to tremendous advances of our understanding of uniquely-human brain development and its response to environmental perturbation. For a molecular biologist focused on understanding the brain and mental illness, this is an exciting time.
MUKUL TEWARY PhD Student, University of Toronto, Toronto, Ontario, Canada
When I read about this workshop being organized by the Company of Biologists on their website, I immediately sent in an application to attend it. My project deals with developing in vitro models of early development using bioengineering technologies. Although, my graduate studies have focused mostly on investigating the induction of mesendodermal tissues, our latest results have diverted my research interests toward studying the ectodermal lineages including the early specification of neural fates. Given that this workshop was focused on in vitro models of neural fates, and that it gave the attendees opportunities to network with the key opinion leaders in the field, I was extremely excited when I was given the chance to attend it.
This workshop far exceeded all my expectations. First and foremost, the organization of the workshop was exceptional! In terms of the content, I truly enjoyed hearing about the extent of progress that has been made in the field of neural organoids. The format that the organizers had chosen included a daily discussion group where the group discussed concerns that the field has and where they think the field is headed. As an early career scientist, I found these sessions incredibly valuable. Notably, one of the scientific concerns that seemed to be prevalent amongst the group was the variability between different pluripotent stem cell lines in generating the downstream organoids. An important aspect of our latest study deals with this very issue and I was very excited to hear that the key opinion leaders in the field are also looking into the same questions.
Overall, this workshop is one of the best meetings I’ve attended, and I would highly recommend these Company of Biologists workshops to everyone but especially to early career scientists.
MIKE FERGUSON MS student, Biomedical Engineering, Boston University, USA
Between the 3, or was it 5 or 6?, course meals, there was indeed great science being discussed! With armfuls (quite literally) of beers being consumed in the “cozy” backroom, great collaborations were set up well past midnight. Set in a victorian mansion, replete with a full time staff, including a most scholarly house historian, this workshop was truly an experience. If you ever wondered what it would be like to be a member of British high society like Barry Lyndon, look no further.
Biologists talking with engineers was the theme. Despite being an engineer and biologist myself, I was exposed to new ideas and ways of thinking nonetheless. For example, what is development? Is it self-assembly or self-organization? Is it special? The most brief of side conversations offered some of the most interesting ideas. Ideas that kept me thinking well after the workshop and have already caused me to take a fresh look at my own work, with good results.
Perhaps the most unique (and truly invaluable) aspect of the workshop was its laid back nature. Participants were encouraged to present unpublished data (non-disclosure was assured). In many ways, it was like a big informal lab meeting. For the young scientists, the workshop is a unique chance to make your name known and your ideas heard. It was a most interesting look into the future, for which I thank the organizers.
All in all, I left disappointed – this being my first real conference that I have attended, all future conferences and workshops are likely to pale in comparison. How many of them will have staff constantly offering you a cup of tea or coffee (an assortment of treats already laid out in the adjacent parlor)?
SAM NAYLER Postdoctoral Fellow, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
What do you get when you take a group of developmental biologists, chemists, bioengineers and neuroscientists away from their daily routines in the lab and put them together in a countryside manor near Brighton, England? The answer is not the punchline to a joke, but instead a seriously productive three days full of introspection and discussion of the pressing issues facing the respective field that unites the interested parties.
The Company of Biologists and conference organisers should be commended on their excellent approach to realizing the formula for a smooth and seamless meeting where inhibitions and impediments to open discussion are rapidly dissolved and a vibrant exchange of ideas and information takes their place. Despite the very formal setting, people were rapidly acquainted and exchanging information and ideas for collaboration. Combined with the fact that everyone presented, and everyone presented unpublished work, allowed for an open and frank forum for discussion. The exposure to fields outside one’s own was an excellent way to survey the current state of play in that field and germinate ideas for collaboration which were later crystallised over a drink in the bar or a walk (or run) in the woods.
There is a proverb that says it takes a village to raise a child. While there is a rich history of developmental biology, the emerging field that uses stem cell science to explore aspects of tissue formation is very much in its infancy, and indeed requires the specialist inputs from the ‘village’ as a whole. To be surrounded by bright, talented and enthusiastic bioinformaticians, biologists and engineers, all of whom have at least temporarily assembled as a village makes me very optimistic about the future of the field going forwards.
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