Development is delighted to announce the third in our highly successful series of events focussing on human developmental biology. Since the initiation of this series, in 2014, we have witnessed huge progress in this field, with more and more researchers turning to stem cell and organoid systems to investigate development and organogenesis in vitro, as well as increased analysis of human embryos and tissues to understand how these processes occur in vivo. Technological advances such as genome editing, single cell sequencing and improvements in tissue engineering now allow us to delve more deeply into the conserved and divergent processes underlying human development. Such knowledge is essential to underpin translational research into developmental disorders and to develop cell and tissue therapies.

This meeting brings together researchers working on a diverse set of questions, united by  common challenges associated with working with human cells and tissues, and by a common goal to understand the similarities and differences between human development and that of other species. As well as talks from invited speakers and selected delegates, the meeting will also include a discussion session on the ethical and legal challenges of working with early human embryos, cells and organoid cultures – and how we as a community should address these.

Registration is open now!

Deadline 22/06/18

Find out more here:

www.biologists.com/meetings/from-stem-cells-to-human-development-september-2018/

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We invite applications for a funded PhD position in the Department of Zoology in Central Cambridge on Downing Street with Dr Stephen Montgomery’s research group.

Project title:

Developmental basis of mushroom body expansion in Heliconius butterflies

Project summary:
Mushroom bodies (MBs) are the most enigmatic structures in the insect brain. They have ‘higher order’ functions, integrating sensory information and storing memories of past experience. MBs share a conserved ground plan, but their size and structure varies extensively across species. MB volume in Heliconius butterflies are among the highest across insects, 3-4 times larger than typical for Lepidoptera, including their most closely related genera in the wider tribe of Heliconiini. This provides a novel system for investigating the developmental mechanisms that control neural proliferation and brain component size. However, nothing is known about the developmental changes that have produced such a dramatic expansion.

What the student will be doing:
The project will involve core laboratory, microscopy and neuroanatomical techniques, insect rearing and experimental manipulation. You will construct the first time course of Heliconius brain development, from late larvae through pupation to adulthood. Using immunocytochemistry and confocal imaging you will determine key properties of MB growth trajectories, providing a template for developing hypotheses of when and how MB development in Heliconius diverged from related genera.
By adopting an evo-devo approach you will then conduct a series of comparative studies across Heliconiini to assess how increases in neuron number are produced, considering four potential mechanisms: i) an increase in the number of neural progenitor cells, ii) accelerated cell-cycle rates during neurogenesis, iii) an extension in the overall duration of neurogenesis including the possibility of adult neurogenesis, iv) reduced or delayed patterns of apoptosis among neural progenitor cells.
Finally, once key periods of developmental divergence have been identified between Heliconius and related genera, you will perform a second series of analyses to identify divergent patterns of gene regulation and expression as part of a project that aims to identify the genetic basis of MB expansion.
Some field/insectary work in Panama may be necessary/desirable. The studentship is funded by the European Research Council for 3.5 years. A student stipend of £14,553 per annum, and tuition fees will be offered to a successful candidate.

FUNDING: The studentship is funded by the European Research Council for 3.5 years. A student stipend of £14,553 per annum, and tuition fees will be offered to a successful candidate.

FURTHER INFORMATION: https://www.zoo.cam.ac.uk/study/postgraduate/phd-and-mphil-studentships/developmental-basis-of-mushroom-body-expansion-in-heliconius-butterflies

APPLICATION DETAILS: Formal applications are welcome until 27th April via the graduate admissions webpage: https://www.graduate.study.cam.ac.uk/how-do-i-apply

Shortlisted candidates will be interviewed in early May and a decision will be made soon after. Informal enquiries to shm37@cam.ac.uk are welcome. For more details see: https://www.zoo.cam.ac.uk/study/postgraduate

RESEARCH GROUP: http://www.shmontgomery.co.uk

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Three-year Postdoc Vacancy: Cell-fate derivation in mouse preimplantation embryo development.

Laboratory of Developmental Biology & Genetics (LDB&G), headed by Alexander W, Bruce Ph.D. – see attached advertisement link.

Interested? Please send your CV, contact details of two professional referees and a motivation letter to: awbruce@prf.jcu.cz

LDB&G Postdoc 2017

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Three months ago I did the unthinkable and moved to England, a strange haggis-free land. Starting my BBSRC PhD Internship (introductory post here) at the Node having left my Scottish lab was an amazing opportunity to get more involved with the dev bio community.

My main task while here was the day to day running of the Node; twitter, jobs and asking authors of interesting papers to write for us, thank you to all the researchers that did! You can read one of my favourite posts on using scRNA-seq to understand cell fate conversion here. I also conducted our people behind the papers interviews and a particular favourite was on the fascinating puzzle of plant cell topology, I even attempted to read On Growth and Form after their interview!

The chance to read and explore such a wide variety of topics has been eye-opening and there is so much fascinating research being conducted on topics I didn’t know existed.  Learning about so many different model systems has shaped my thinking about my future in research (any Cephalopod neurobiology labs needing a Postdoc soon?).

Alongside keeping the Node running, my second project focused on refurbishing the resources section on the Node. My goal here was to make use of my position as an active researcher to make the resources page a community area to find useful links for research, teaching and to encourage researchers to engage in outreach ad advocacy.  This resources list is by no means comprehensive and we still need your input.  Please get in touch to let us know what is useful to you, what needs to be added/updated and any way that the resources section can be improved!

This internship has been a wonderful insight into the developmental biology community and I am so grateful to Aidan and Katherine for the opportunity and their guidance throughout the three months. I encourage all researchers to write for the Node, get your research out there! I am now returning to my PhD, all that is left to say is so long and thanks for all the Zebrafish.

Sarah

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A discussion of our recent paper: Annick Sawala & Alex P. Gould (2017). The sex of specific neurons controls female body growth in Drosophila. PLoS Biology, October 4 2017.

In the beginning…

The story behind this study provides yet another example of where the pursuit of a few chance observations developed into an interesting project in its own right.

I started my postdoc in the lab of Alex Gould at The Francis Crick Institute with the objective of investigating how nutrient deprivation affects the growth of different body parts of the fruit fly larva. These experiments required precise measurements of organ sizes, and it soon became pretty clear that in order to get the most useful data, males and females had to be analysed separately. Not because the different sexes necessarily show different growth responses to starvation, but because female body parts are consistently 20-40% larger than their male counterparts. Hence, if males and females are pooled, the data have a large variance. Surprisingly, a lot of studies that have analysed larval growth seem to have ignored this sex difference in body size, officially termed sexual size dimorphism (SSD). So SSD effectively doubled my workload but it also opened up a new question: how does the sex of the larva influence its growth?

Summary of the key findings

We used two opposite angles of attack to identify the mechanism underlying larval SSD. First, in a sort of top-down approach, we asked if there were any measurable differences in growth parameters or behaviour that could give insights into underlying genetic mechanisms. Second, using a bottom-up strategy, we manipulated sex determination genes in individual cell types to see if the sex of a specific body part influenced overall body size.

For the first approach, I painstakingly weighed individual male and female larvae at different stages in order to determine their growth curves. When a larva hatches from the embryo it only weighs around 10mg, about 1/5^th of the mass of a grain of salt! [1], and it grows to a final size of about ~2mg, around half the mass of a sesame seed [2], before it undergoes pupal development about 4 days later. This work established that males and females have the same size at larval hatching and that they have similar time windows of growth. Nevertheless, females begin to have a higher growth rate from about the middle of the second larval instar onwards. Interestingly, I found that the greatest difference in the fold rate of growth between the sexes occurs relatively early in larval development, during the second larval instar. This means that any pathways that control sex differences in body size should be active before or during the second larval instar.

For the second approach, we used the amazing GAL4/UAS system of Brand and Perrimon [3] to manipulate a gene called Sex-lethal (Sxl), the master regulator of fly sex determination. Sxl is normally only expressed in females, and it directs the sex-specific splicing of downstream genes in order to specify the development of female morphology and behaviour (Fig 1). Sxl mutant females are masculinised both in terms of their morphology and their body size, demonstrating that Sxl controls SSD by promoting higher female growth.

I used RNAi to inhibit Sxl expression in different tissues and, strikingly, found that knockdown with a pan-neuronal Gal4 driver reduced the body size of females to that of males (Fig 2A). In the reverse experiment, restoring Sxl expression in neurons could partially rescue the female body size of Sxl mutants. Thus, Sxl acts in neurons in a non-cell autonomous manner to boost the growth of the female body. To pinpoint the neuronal population in which Sxl functions to promote SSD, a panel of neuronal subset-specific Gal4 drivers were then screened. We found that Sxl acts additively in at least two non-overlapping subsets of neurons: 1) the insulin producing cells (IPCs), a cluster of 7 neurosecretory cells that are known to secrete several insulin-like peptides into the circulation, and 2) cells expressing the Gad1-Gal4 driver, which is active in GABAergic neurons (although we found that the overlap with GABA-expressing neurons is only partial).

The results of both approaches raise four tricky questions that Alex and I have been thinking about, and also investigating, with varying levels of success:

How does the new study fit with the dogma that somatic sex determination in flies is cell-autonomous?

We think the answer to this important question lies in differences between how Sxl regulates the SSD of the larval versus the adult body. On the face of it, our finding that Sxl acts in neurons to increase female body growth would seem to conflict with classic genetic studies of gynandromorphs (flies mosaic for male and female cells). These sex mosaic flies had clearly demonstrated that male/female morphologies are controlled cell-autonomously. Not only that but, in a bilateral gynandromorph, the male side is smaller than the female side [4] (Fig 3). So how can we square the classic findings with our new observations?

The first thing to note is that the presence of the cell-autonomous effects revealed by gynandromorphs does not completely rule out additional non-cell autonomous effects. In fact, such a dual SSD mechanism does seem to operate in mammals. For example, a recent mouse study suggests that gonadal hormones and direct effects of sex chromosomes combine to produce overall differences in growth and metabolism between males and females [5, 6]. Furthermore, we and others [7, 8] have found that manipulation of Sxl or its downstream target transformer does indeed have cell-autonomous effects on growth, although they are too small to account for the full extent of SSD.

Secondly, we realised that the gynandromorph studies only looked at the external structures of the adult fly. These are derived from small groups of diploid cells called imaginal discs, which grow within the larval body and only transform into adult structures during metamorphosis. In contrast, I had measured SSD for the larval body itself, the bulk of which is composed of large polyploid cells, which are degraded during metamorphosis and so do not make it to the final fly. This realization led to the testable hypothesis that SSD is regulated differently in the larval polyploid tissues versus the diploid imaginal tissues. Unlike many of our crazy hypotheses, this one turned out to stand the test of time as neuronal knockdown of Sxl abolished SSD in the fat body (a larval tissue), yet it had no effect on SSD in the wing imaginal disc (the adult wing precursor) (Fig 2B and 2C). Thus, neuronal Sxl in females specifically boosts the growth of larval not imaginal tissues during the period of juvenile development. Nevertheless, by the time the imaginal discs have transformed into the mature external structures of the adult fly, I did observe a moderate effect of neuronal Sxl knockdown on SSD (Fig 2D). To account for this, we propose that, by promoting larval tissue growth, neuronal Sxl also indirectly boosts the growth of imaginal tissues, because a larger larval body confers increased pupal resources (nutrients and/or growth factors) to sustain the growth of imaginal structures during pupal stages. An alternative explanation, which we cannot rule out for now, is that neuronal Sxl also acts during pupal stages to directly influence the size of imaginal structures.

Is there a role for insulin signalling in SSD?

We think the overall answer to this question is “yes but only for imaginal tissues” and here’s our logic for why this may be the case. Sxl functions in insulin producing cells and it is known that insulin secretion from these cells is a key regulator for growth, so an attractive hypothesis is that Sxl promotes insulin secretion in females, thereby boosting female growth. Interestingly, SSD in mammals is driven in part by gonadal hormones causing sex differences in insulin-like growth factor 1 (IGF-1) release. However, our data suggest that SSD of the larval body (i.e. the target of neuronal Sxl) is established independently of sex differences in insulin signalling. This is because, at the early stages when the sex difference in growth rates is maximal (the second instar larva), no sex differences in insulin secretion or insulin signalling could be detected. In addition, several manipulations aimed at changing insulin secretion from IPCs also had no effect on larval body SSD. And finally, mutant larvae that lack one or all of the insulin-like peptides (Ilps) produced in the insulin producing cells are very small yet their SSD remains intact. These findings suggest to us that Ilps are not required for the establishment of sex differences in growth in the early larva.

But the twist here is that there is evidence suggesting a role for insulin signalling in SSD in older larvae and in adult flies. Thus, insulin receptor mutant adult flies show a strong reduction in SSD (measured as dry body mass) [9]. At late larval stages, it has also been reported that insulin secretion from IPCs and insulin signalling is higher in females [7]. It is therefore likely that sex differences in insulin signalling in old larvae contribute to SSD in imaginal tissues, even though at this time larval body growth has largely finished. In support of this, I found that when IPCs are genetically manipulated to decrease their size and so presumably their insulin secretion, SSD is abolished in the wing imaginal disc but it remains intact in the larval body, despite the smaller absolute body masses of both sexes. Clearly, more work is needed to understand why insulin signalling appears to regulate the SSD of larval versus imaginal tissues so differently.

What is downstream of neuronal Sxl to boost female body growth?

We wish we could answer this tricky question but, unfortunately, all we can give you right now is a list of factors that are probably NOT involved.

As mentioned above, the current evidence indicates that insulin like peptides are not strong candidates for the Sxl targets in IPCs that are relevant for establishing larval body SSD. Nevertheless, it is possible that Sxl regulates the secretion of other signalling molecule(s) into the circulation, either directly from IPCs, or from cells that the IPC neurons connect with. Notably, IPCs send axons to the ring gland [10, 11], a major hemosecretory organ, which could provide such a systemic signal. The role of Sxl in the Gad1-Gal4 neurons is even less clear.

Two direct downstream targets of Sxl that have been widely studied are transformer and msl-2 (see Fig 1). Our loss of function and rescue experiments strongly suggest that neither transformer nor msl-2 play a role in the neurons regulating larval SSD. The msl-2 data also ruled out the possibility that the reduction in female body sizes we saw in Sxl loss of function experiments were due to “sickness” caused by ectopic activation of msl-2 expression and the dosage compensation machinery.  It is likely that a new Sxl target is involved, but identification of this may well require unbiased sequencing experiments or other genome-wide techniques, using brains from the relevant developmental stage.

Is increased female body growth driven by increased feeding?

We have been asked this question a lot at conferences. We did measure feeding rates in early second and early third instar larvae. In both cases, sex differences in the absolute food intake rate (i.e. intake per larva) were detected, but when these were normalised for body mass, mass-specific food intake rates (i.e intake per mg of larval tissue) appear to be the same for males and females. This suggests to us that sex differences in absolute food intake are a consequence of a larger female body mass, but not the driver of it. So why then do female larvae have a higher mass-specific (i.e. fold) growth rate than males despite both sexes having similar mass-specific feeding rates? One possible explanation here is that female larvae are more efficient at converting nutrients into tissue mass than males.

It is important to highlight that there are caveats to our conclusion that mass-specific food intake is equal in male versus female larvae. This is because we measured food intake over 20-30 minutes using a blue dye uptake method that would not be sensitive enough to detect very small differences. Some clever method for measuring food consumption over much longer periods might be necessary to detect very small sex differences in mass-specific food intake. Unfortunately, this may be tricky as larvae not only eat their food but they also burrow in it, and defecate into it. However, there is another reason for thinking that the neuronal Sxl mechanism for establishing SSD does not involve sex-specific feeding. This is because increased feeding rates in females would be predicted to increase the growth of both larval and imaginal tissues, yet we observed that imaginal tissues inside the larva are blind to neuronal Sxl regulation.

Concluding remarks

Sex determination and growth regulation have been extensively studied in Drosophila for many years. It is therefore very surprising that only a handful of studies have investigated how sex influences growth in this model organism. The neuronal Sxl relay mechanism that we have recently discovered contrasts with the text book view that somatic sexual differentiation in insects is controlled in a strictly cell-autonomous fashion. Future research into the neuronal Sxl mechanism for larval SSD will be needed to identify the relevant Sxl targets and perhaps endocrine growth regulatory mechanisms that act selectively on larval polyploid tissues rather than diploid imaginal discs.  Despite this, our research has already revealed glimpses that suggest that the regulatory logic of SSD in mammals and insects may be more similar than previously thought. This encouraging news opens up the possibility of using our favourite model organism to study how sex differences in growth and metabolism impact upon disease – an important emerging area of biomedical research.

References

1. “Grain of salt”: Bluebulb Projects’ The Measure of Things; [02.12.2017]. Available here.
2. “Sesame seed” [02.12.2017]. Available here.
3. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118(2):401-15.
4. Morgan THB, C.B. I. The Origin of Gynandromorphs. Contributions to the genetics of Drosophila melanogaster. 278: Publs Carnegie Instn; 1912. p. 1-122.
5. Chen X, McClusky R, Chen J, Beaven SW, Tontonoz P, Arnold AP, et al. The number of x chromosomes causes sex differences in adiposity in mice. PLoS Genet. 2012;8(5):e1002709. doi: 10.1371/journal.pgen.1002709.
6. Arnold AP, Chen X, Link JC, Itoh Y, Reue K. Cell-autonomous sex determination outside of the gonad. Dev Dyn. 2013;242(4):371-9. doi: 10.1002/dvdy.23936.
7. Rideout EJ, Narsaiya MS, Grewal SS. The Sex Determination Gene transformer Regulates Male-Female Differences in Drosophila Body Size. PLoS Genet. 2015;11(12):e1005683. doi: 10.1371/journal.pgen.1005683.
8. Regan JC, Khericha M, Dobson AJ, Bolukbasi E, Rattanavirotkul N, Partridge L. Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction. Elife. 2016;5:e10956. doi: 10.7554/eLife.10956.
9. Testa ND, Ghosh SM, Shingleton AW. Sex-Specific Weight Loss Mediates Sexual Size Dimorphism in Drosophila melanogaster. PLoS One. 2013;8(3):e58936-e. doi: 10.1371/journal.pone.0058936.
10. Rulifson EJ, Kim SK, Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science. 2002;296(5570):1118-20. doi: 10.1126/science.1070058.
11. Cao J, Ni JL, Ma WX, Shiu V, Milla LA, Park S, et al. Insight into Insulin Secretion from Transcriptome and Genetic Analysis of Insulin-Producing Cells of Drosophila. Genetics. 2014;197(1):175-92. doi: 10.1534/genetics.113.160663.

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Our latest monthly trawl for developmental biology (and other cool) preprints. Let us know if we missed anything.

This month in preprint news – here at The Company of Biologists, set just outside Cambridge in the UK, we’re hiring a new ‘Preprints Community Manager’. You can find out more here. It’s a great opportunity to get in to science communication and publishing, and of course preprints!

And this month in preprints, we found platypuses and pigeons, xenotransplants and reoriented axes,  CRISPR tools and liquid droplets. The preprints were hosted on bioRxiv, PeerJ, and arXiv. Use these links to get to the section you want:

Developmental biology

| Patterning & signalling

| Morphogenesis & mechanics

| Genes & genomes

| Stem cells, regeneration & disease modelling

Evo-devo & evo

Cell biology

Modelling

Tools & resources

| Imaging etc.

| Genome tools

Research practice

Why not…

Developmental biology

| Patterning & signalling

Reorientation of the primary body axis by ectopic embryonic cWnt signaling. Mark Q Martindale, Naveen Wijesena

High fidelity lineage tracing in mouse pre-implantation embryos using primed conversion of photoconvertible proteins. Maaike Welling,  Manuel A. Mohr, Aaron Ponti, Lluc R. Sabater, Andrea Boni, Prisca Liberali, Pawel Pelczar, Periklis Pantazis

Caudal counter-represses Hunchback to regulate even-skipped stripe 2 expression in Drosophila embryos. Ben J Vincent, Max V Staller, Francheska Lopez-Rivera, Meghan DJ Bragdon, Zeba Wunderlich, Javier Estrada, Angela H DePace

A damped oscillator imposes temporal order on posterior gap gene expression in Drosophila. Berta Verd, Erik Clark, Karl R. Wotton, Hilde Janssens, Eva Jimenez-Guri, Anton Crombach, Johannes Jaeger

From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo. Daria Gavriouchkina, Ruth M Williams, Martyna Lukoseviciute, Tatiana Hochgreb-Hagele, Upeka Senanayake, Vanessa Chong-Morrison, Supat Thongjuea, Emmanouela Repapi, Adam Mead, Tatjana Sauka-Spengler

Embryonic circular RNAs at tandem duplicated genes in zebrafish present new paradigm in gene expression. Vanessa Chong-Morrison, Tatjana Sauka-Spengler

Diversification of heart progenitor cells by EGF signaling and differential modulation of ETS protein activity. Benjamin Schwarz, Dominik Hollfelder, Katharina Scharf, Leonie Hartmann, Ingolf Reim

Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement. Guangshuai Jia, Jens Preussner, Stefan Guenther, Xuejun Yuan, Michail Yekelchyk, Carsten Kuenne, Mario Looso, Yonggang Zhou, Thomas Braun

Early Subset Of Cerebellar Nuclei Neurons Derived From Mesencephalon In Mice. Maryam Rahimi-Balaei, Xiaodan Jiao, Fiona Parkinson, Behzad Yeganeh, Hassan Marzban

Elevated and sustained reactive oxygen species levels facilitate mesoderm formation during early Xenopus development. Yue Han, Yaoyao Chen, Nick R Love, Shoko Ishibashi, Enrique Amaya

Ca2+-induced mitochondrial ROS regulate the early embryonic cell cycle. Yue Han, Shoko Ishibashi, Javier Iglesias-Gonzalez, Yaoyao Chen, Nick R Love, Enrique Amaya

Proteomics of phosphorylation and protein dynamics during fertilization and meiotic exit in the Xenopus egg. Marc Stuart Presler, Elizabeth Van Itallie, Allon M. Klein, Ryan Kunz, Peg Coughlin, Leonid Peshkin, Steven Gygi, Martin Wühr, Marc Kirschner

Maternal proteins that are phospho-regulated upon egg activation include crucial factors for oogenesis, egg activation and embryogenesis in Drosophila melanogaster. Zijing Zhang, Amber R. Krauchunas, Stephanie Huang, Mariana F. Wolfner

Endodermal differentiation is reconstructed by coordination of two parallel signaling systems derived from the stele in roots. Pengxue Li, Qiaozhi Yu, Chunmiao Xu, Xu Gu, Shilian Qi, Hong Wang, Fenglin Zhong, Shuang Wu

Minimum requirements for reprogramming and maintaining cell fate in the Arabidopsis root. Colleen Drapek, Erin E. Sparks, Peter Marhavy, Tonni G. Andersen, Jessica H. Hennacy, Niko Geldner, Philip N. Benfey

LRX Proteins play a crucial role in pollen grain and pollen tube cell wall development. Tohnyui Ndinyanka Fabrice, Hannes Vogler, Christian Draeger, Gautam Munglani, Shibu Gupta, Aline Galatea Herger, Paul Knox, Ueli Grossniklaus, Christoph Ringli

Hominin-specific NOTCH2 paralogs expand human cortical neurogenesis through regulation of Delta/Notch interactions. Ikuo K Suzuki, David Gacquer, Roxane Van Heurck, Devesh Kumar, Marta Wojno, Angeline Bilheu, Adele Herpoel, Julian Cheron, Franck Polleux, Vincent Detours, Pierre Vanderhaeghen

Human-specific NOTCH-like genes in a region linked to neurodevelopmental disorders affect cortical neurogenesis. Ian T Fiddes, Gerrald A Lodewijk, Meghan M Mooring, Colleen M Bosworth, Adam D Ewing, Gary L Mantalas, Adam M Novak, Anouk van den Bout, Alex Bishara, Jimi L Rosenkrantz, Ryan Lorig-Roach, Andrew R Field, Maximillian Haeussler, Lotte Russo, Aparna Bhaduri, Tomasz J Nowakowski, Alex A Pollen, Max L Dougherth, Xander Nuttle, Marie-Claude Addor, Simon Zwolinski, Sol Katzman, Arnold Kreigstein, Evan E Eichler, Sofie R Salama, Frank MJ Jacobs, David Haussler

Skeletal muscle fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH-dependent regulation of adipogenesis. Milica Marinkovic, Francesca Sacco, Filomena Spada, Lucia Lisa Petrilli, Claudia Fuoco, Elisa Micarelli, Theodora Pavlidou, Luisa Castagnoli, Matthias Mann, Cesare Gargioli, Gianni Cesareni

NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence. Aled J Parry, Matthew Hoare, Dóra Bihary, Robert Hänsel-Hertsch, Stephen Smith, Kosuke Tomimatsu, Shankar Balasubramanian, Hiroshi Kimura, Shamith Samarajiwa, Masashi Narita

Altered hsrω lncRNA levels in activated Ras background further enhance Ras activity in Drosophila eye and induces more R7 photoreceptors. Subhash C Lakhotia, Mukulika Ray

An atlas of Caenorhabditis elegans chemoreceptor expression. Berta Vidal, Ulkar Aghayeva, Haosheng Sun, Chen Wang, Lori Glenwinkel, Emily Bayer, Oliver Hobert

Bidirectional Cycling Dynamics of Living Neuronal Networks in Vitro. Arseniy Gladkov, Oleg Grinchuk, Yana Pigareva, Irina Mukhina, Victor Kazantsev, Alexey Pimashkin

Loss of Wt1 in the murine spinal cord alters interneuron composition and locomotion. Danny Schnerwitzki, Sharn Perry, Anna Ivanova, Fabio Viegas Caixeta, Paul Cramer, Sven Guenther, Kathrin Weber, Atieh Tafreshiha, Lore Becker, Ingrid L. Vargas Panesso, Thomas Klopstock, Martin Hrabe de Angelis, Manuela Schmidt, Klas Kullander, Christoph Englert

Smad9 is a key player of follicular selection in goose via keeping the balance of LHR transcription. Daolun Yu, Fanghui Chen, Li Zhang, Hejian Wang, Jie Chen, Zongmeng Zhang, Jie Li, Chaofeng Xing, Honglin Li, Jun Li, Yafei Cai

Widespread dynamic and pleiotropic expression of the melanocortin-1-receptor (MC1R) system is conserved across chick, mouse and human embryonic development. Anna Thomas, Pauline Heux, Chloe Santos, Wisenave Arulvasan, Nita Solanky, Magalie E. Carey, Dianne Gerrelli, Veronica A. Kinsler, Heather C. Etchevers

| Morphogenesis & mechanics

Size-reduced embryos reveal a gradient scaling based mechanism for zebrafish somite formation. Kana Ishimatsu, Tom W Hiscock, Zach M Collins, Dini Wahyu Kartika Sari, Kenny Lischer, David L. Richmond, Yasumasa Bessho, Takaaki Matsui, Sean G Megason

Spatio-temporal elasticity patterns in extracellular matrix during Hydra morphogenesis. Mariam Veschgini, Hendrik O Petersen, Wasim Abuillan, Fernanda F Rossetti, Suat Özbek, Manfred Burghammer, Thomas W Holstein, Motomu Tanaka

Selective Filopodia Adhesion Ensures Robust Cell Matching in the Drosophila Heart. ShaoBo Zhang, Christopher Amourda, Timothy Saunders

Junction-based lamellipodia drive endothelial cell rearrangements in vivo via a VE-cadherin/F-actin based oscillatory ratchet mechanism. Ilkka Paatero, Loic Sauteur, MInkyoung Lee, Anne Karine Lagendijk, Daniel Heutschi, Dimitri Bieli, Benjamin M. Hogan, Markus Affolter, Heinz-Georg Belting

Actomyosin contractility modulates Wnt signaling through adherens junction stability. Eric T. Hall, Elizabeth A. Hoesing, Endre D. Sinkovics, Esther M. Verheyen

PI(4,5)P2 forms dynamic cortical structures and directs actin distribution and cell polarity in C. elegans embryos. Melina J. Scholze, Kevin S. Barbieux, Alessandro De Simone, Mathilde Boumasmoud, Camille C. N. Suess, Ruijia Wang, Pierre Gonczy

Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture. Colin D. Donohoe, Andreia Correia, Gabor Csordas, Marek Jindra, Corinna Klein, Bianca Habermann, Mirka Uhlirova

Cerebellar granule cell precursors can extend processes, undergo short migratory movements and express postmitotic markers before mitosis in the chick EGL. Michalina Hanzel, Richard JT Wingate

Axons from the trigeminal ganglia are the earliest afferent projections to the mouse cerebellum. Hassan Marzban, Maryam Rahimi Balaei, Richard Hawkes

Formin3 regulates dendritic architecture via microtubule stabilization and is required for somatosensory nociceptive behavior. Ravi Das, Jamin M Letcher, Jenna M Harris, Istvan Foldi, Sumit Nanda, Hansley M Bobo, József Mihály, Giorgio A Ascoli, Daniel N Cox

Effects of mutating α-tubulin lysine 40 on sensory dendrite development. Brian Jenkins, Harriet A. J. Saunders, Helena L. Record, Dena M. Johnson-Schlitz, Jill Wildonger

Anisotropic Cellular Mechanoresponse for Radial Size Maintenance of Developing Epithelial Tubes. Tsuyoshi Hirashima, Taiji Adachi

Live imaging of heart tube development in mouse reveals alternating phases of cardiac differentiation and morphogenesis. Kenzo Ivanovitch, Susana Temino, Miguel Torres

| Genes & genomes

Transgenerational Epigenetic Inheritance Factors Localize to Spatially and Temporally Ordered Liquid Droplet Assemblages. Gang Wan, Brandon Fields, George Spracklin, Carolyn Phillips, Scott Kennedy

Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics. Andreas Sagner, Zachary Gaber, Julien Delile, Jennifer H. Kong, David L. Rousso, Caroline A. Pearson, Steven E. Weicksel, Manuela Melchionda, Neda Mousavy Gharavy, James Briscoe, Bennett Novitch

Integrated analysis of single-cell embryo data yields a unified transcriptome signature for the human preimplantation epiblast. Giuliano G Stirparo, Thorsten Boroviak, Ge Guo, Jennifer Nichols, Austin Smith, Paul Bertone

Allele-specific control of replication timing and genome organization during development. Juan Carlos Rivera-Mulia, Andrew Dimond, Daniel Vera, Claudia Trevilla-Garcia, Takayo Sasaki, Jared Zimmerman, Catherine Dupont, Joost Gribnau, Peter Fraser, David M Gilbert

The conserved LEM-3/Ankle1 nuclease is involved in the combinatorial regulation of meiotic recombination repair and chromosome segregation in Caenorhabditis elegans. YE HONG, Maria Velkova, Nicola Silva, Marlene Jagut, Viktor Scheidt, Karim Labib, Verena Jantsch, Anton Gartner

Re-arrangements in the cytoplasmic distribution of small RNAs following the maternal-to-zygotic transition in Drosophila embryos. Mehmet Ilyas Cosacak, Hatice Yigit, Bunyamin Akgul

Smg5 is required for multiple nonsense-mediated mRNA decay pathways in Drosophila. Jonathan O. Nelson, Dominique Foerster, Kimberly Frizzell, Stefan Luschnig, Mark M. Metzstein

Quantitative RNAseq Meta Analysis Of Alternative Exon Usage In C. elegans. Nicolas J. Tourasse, Jonathan R. M. Millet, Denis Dupuy

Dynamic reorganization of nuclear architecture during human cardiogenesis. Paul A Fields, Vijay Ramani, Giancarlo Bonora, Galip Gurkan Yardimci, Alessandro Bertero, Hans Reinecke, Lil Pabon, William S Noble, Jay Shendure, Charles Murry

Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues. Erin E. Terry, Xiping Zhang, Christy Hoffmann, Laura D. Hughes, Scott A. Lewis, Jiajia Li, Lance Riley, Nicholas F. Lahens, Ming Gong, Francisco Andrade, Karyn A. Esser, Michael E. Hughes

Deciphering cis-regulatory logic with 100 million synthetic promoters. Carl de Boer, Ronen Sadeh, Nir Friedman, Aviv Regev

Spatially varying cis-regulatory divergence in Drosophila embryos elucidates cis-regulatory logic. Peter A. Combs, Hunter B. Fraser

Determinants of Transcription Initiation Directionality in Metazoans. Mahmoud M Ibrahim, Aslihan Karabacak, Alexander Glahs, Ena Kolundzic, Antje Hirsekorn, Alexa Carda, Baris Tursun, Robert P Zinzen, Scott A Lacadie, Uwe Ohler

Transcription start site analysis reveals widespread divergent transcription in D. melanogaster and core promoter encoded enhancer activities. Sarah Rennie, Maria Dalby, Marta Lloret-Llinares, Stylianos Bakoulis, Christian Dalager Vaagenso, Torben Heick Jensen, Robin Andersson

Higher-order inter-chromosomal hubs shape 3-dimensional genome organization in the nucleus. Sofia A Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason Lai, Alexander Shishkin, Prashant Bhat, Vickie Trinh, Erik Aznauryan, Pamela Russell, Christine Cheng, Marko Jovanovic, Amy Chow, Patrick McDonel, Manuel Garber, Mitchell Guttman

CHRAC/ACF Contribute to the Repressive Ground State of Chromatin. Alessandro Scacchetti, Laura Brueckner, Dhawal Jain, Tamas Schauer, Xu Zhang, Frank Schnorrer, Bas van Steensel, Tobias Straub, Peter B. Becker

Strong binding activity of few transcription factors is a major determinant of open chromatin. Bei Wei, Arttu Jolma, Biswajyoti Sahu, Lukas M. Orre, Fan Zhong, Fangjie Zhu, Teemu Kivioja, Inderpreet Kaur Sur, Janne Lehtio, Minna Taipale, Jussi Taipale

Chromatin-release of the long ncRNA A-ROD is required for transcriptional activation of its target gene DKK1. Evgenia Ntini, Julia Liz, Jose M Muino, Annalisa Marsico, Ulf Andersson Oerom

LEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during cytokinesis. YE HONG, Remi Sonneville, Bin Wang, Viktor Scheidt, Bettina Meier, Alexander Woglar, Sarah Demetriou, Karim Labib, Verena Jantsch, Anton Gartner

Profiling of accessible chromatin regions across multiple plant species and cell types reveals common gene regulatory principles and new control modules. Kelsey A. Maher, Marko Bajic, Kaisa Kajala, Mauricio Reynoso, Germain Pauluzzi, Donnelly A. West, Kristina Zumstein, Margaret Woodhouse, Kerry Bubb, Mike Dorrity, Christine Queitsch, Julia Bailey-Serres, Neelima Sinha, Siobhan M. Brady, Roger B. Deal

Chromatin accessibility changes between Arabidopsis stem cells and mesophyll cells illuminate cell type-specific transcription factor networks. Paja Sijacic, Marko Bajic, Elizabeth C. McKinney, Richard B. Meagher, Roger B. Deal

Distinct types of short open reading frames are translated in plant cells. Igor Fesenko, Ilya Kirov, Andrey Kniazev, Regina Khazigaleeva, Vassili Lazarev, Daria Kharlampieva, Ekaterina Grafskaia, Viktor Zgoda, Ivan Butenko, Georgy Arapidi, Anna Mamaeva, Vadim Ivanov, Vadim Govorun

Distinct stimulatory mechanisms regulate the catalytic activity of Polycomb Repressive Complex 2 (PRC2). Chul-Hwan Lee, Marlene Holder, Daniel Grau, Ricardo Saldana-Meyer, Rais Ahmad Ganai, Jenny Zhang, Miao Wang, Marc-Werner Dobenecker, Danny Reinberg, Karim-Jean Armache

Functional redundancy of variant and canonical histone H3 lysine 9 modification in Drosophila. Taylor J. R. Penke, Daniel J. McKay, Brian D. Strahl, A. Gregory Matera, Robert J. Duronio

The function of the prereplicative complex and SCF complex components during Drosophila wing development. Hidetsugu Kohzaki

PWO1 interacts with PcG proteins and histones to regulate Arabidopsis flowering and development. Mareike L Hohenstatt, Pawel Mikulski, Olga Komarynets, Constanze Klose, Ina Kycia, Albert Jeltsch, Sara Farrona, Daniel Schubert

PWWP INTERACTOR OF POLYCOMBS (PWO1) links PcG-mediated gene repression to the nuclear lamina in Arabidopsis. Pawel Mikulski, Mareike L Hohenstatt, Sara Farrona, Cezary Smaczniak, Kerstin Kaufmann, Gerco Angenent, Daniel Schubert

The HoxD Cluster is a Dynamic and Resilient TAD Boundary Controling the Segregation of Antagonistic Regulatory Landscapes. Eddie Rodriguez-Carballo, Lucille Lopez-Delisle, Ye Zhan, Pierre Fabre, Leonardo Beccari, Imane El-Idrissi, Thi Hahn Nguyen Huynh, Hakan Ozadam, Job Dekker, Denis Duboule

Cohesin facilitates zygotic genome activation in zebrafish. Michael Meier, Jenny Grant, Amy Dowdle, Amarni Thomas, Jennifer E. Gerton, Philippe Collas, Justin M. O’Sullivan, Julia A. Horsfield

CTCF mediated genome architecture regulates the dosage of mitotically stable mono-allelic expression of autosomal genes. Keerthivasan Raanin Chandradoss, Kuljeet Singh Sandhu

Interdependent and separable functions of C. elegans MRN-C complex members couple formation and repair of meiotic DSBs. Chloe Girard, Baptiste Roelens, Karl A. Zawadzki, Anne M. Villeneuve

LINE-2 transposable elements shape post-transcriptional gene regulation in the human brain. Rebecca Petri, Per Ludvik Brattås, Marie E. Jönsson, Karolina Pircs, Johan Bengzon, Johan Jakobsson

No kissing in the nucleus: Unbiased analysis reveals no evidence of trans chromosomal regulation of mammalian immune development. Timothy M Johanson, Hannah D Coughlan, Aaron TL Lun, Naiara G Bediaga, Gaetano Naselli, Alexandra L Garnham, Leonard C Harrison, Gordon K Smyth, Rhys S Allan

The Transcriptional Logic of Mammalian Neuronal Diversity. Ken Sugino, Erin Clark, Anton Schulmann, Yasuyuki Shima, Lihua Wang, David L. Hunt, Bryan M. Hooks, Dimitri Trankner, Jayaram Chandrashekar, Serge Picard, Andrew Lemire, Nelson Spruston, Adam Hantman, Sacha B. Nelson

| Stem cells, regeneration & disease modelling

Signaling-dependent control of apical membrane size and self-renewal in rosette-stage human neuroepithelial stem cells. Jan-Philip Medelnik, Kathleen Roensch, Satoshi Okawa, Antonio del Sol, Osvaldo Chara, Levan Mchedlishvili, Elly Tanaka

Fractone bulbs derive from ependymal cells and their laminin composition influence the stem cell niche in the subventricular zone. Marcos Assis Nascimento, Lydia Sorokin, Tatiana Coelho-Sampaio

Comparison of reprogramming factor targets reveals both species-specific and conserved mechanisms in early iPS cells. Kai Fu, Constantinos Chronis, Abdenour Soufi, Giancarlo Bonora, Miguel Edwards, Steve Smale, Kenneth Zaret, Kathrin Plath, Matteo Pellegrini

Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche. Enrique Sosa, Di Chen, Ernesto J Rojas, Jon Hennebold, Karen Peters, Zhuang Wu, Truong N Lam, Jennifer Mitchell, Ramesh Tailor, Marvin Meistrich, Kyle Orwig, Gunapala Shetty, Amander T Clark

Temporal epigenomic profiling identifies AHR as dynamic super-enhancer controlled regulator of mesenchymal multipotency. Deborah Gerard, Florian Schmidt, Aurelien Ginolhac, Martine Schmitz, Rashi Halder, Peter Ebert, Marcel H. Schulz, Thomas Sauter, Lasse Sinkkonen

Comparison of multiple transcriptomes exposes unified and divergent features of quiescent and activated skeletal muscle stem cells. Natalia Pietrosemoli, Sebastien Mella, Siham Yennek, Meryem Baghdadi, Hiroshi Sakai, Ramkumar Sambasivan, Francesca Pala, DANIELA DI GIROLAMO, Shahragim Tajbakhsh

Single-cell quantitative analysis of skeletal muscle cell population dynamics during regeneration and ageing. Lucia Lisa Petrilli, Filomena Spada, Claudia Fuoco, Elisa Micarelli, Alessio Reggio, Marco Rosina, Cesare Gargioli, Luisa Castagnoli, Gianni Cesareni

Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age. Mati Mann, Arnav Mehta, Carl de Boer, Monika S. Kowalczyk, Kevin Lee, Noga Rogel, Abigail R. Knecht, Daneyal Farouq, Aviv Regev, David Baltimore

T helper cells modulate intestinal stem cell renewal and differentiation. Moshe Biton, Adam Haber, Semir Beyaz, Noga Rogel, Christopher Smillie, Karthik Shekhar, Alexandra Schnell, Zuojia Chen, Chuan Wu, Jose Ordovas-Montanes, David Alvarez, Rebecca H. Herbst, Itay Tirosh, Grace Burgin, Danielle Dionne, Michael E. Xifaras, Mei Zhang, Alex K. Shalek, Ulrich H. von Andrian, Daniel B. Graham, Orit Rozenblatt-Rosen, Hai Ning Shi, Vijay Kuchroo, Omer Yilmaz, Aviv Regev, Ramnik J. Xavier

The CD11a and EPCR marker combination simplifies and improves the purification of mouse hematopoietic stem cells. Alborz Karimzadeh, Vanessa Scarfone, Connie Chao, Karin Grathwohl, John W. Fathman, David Fruman, Thomas Serwold, Matthew Inla

Instructive starPEG-Heparin biohybrid 3D cultures for modeling human neural stem cell plasticity, neurogenesis, and neurodegeneration. Christos Papadimitriou, Mehmet I Cosacak, Violeta Mashkaryan, Hilal Celikkaya, Laura Bray, Prabesh Bhattarai, Heike Hollak, Xin Chen, Shuijin He, Christopher L Antos, Alvin Thomas, Jens Friedrichs, Andreas Dahl, Yixin Zhang, Uwe Freudenberg, Carsten Werner, Caghan Kizil

Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging. Jiahn Choi, Nikolai Rakhilin, Poornima Gadamsetty, Daniel J. Joe, Tahmineh Tabrizian, Steven M. Lipkin, Derek Huffman, Xiling Shen, Nozomi Nishimura

Generation of Mouse-Zebrafish Hematopoietic Tissue Chimeric Embryos for Hematopoiesis and Host-Pathogen Interaction Studies. Margarita M. Parada-Kusz, Anne Clatworthy, Elliott J. Hagedorn, Cristina Penaranda, Anil V. Nair, Jonathan E. Henninger, Christoph Ernst, Brian Li, Raquel Riquelme, Humberto Jijon, Eduardo J. Villablanca, Leonard I. Zon, Deborah Hung, Miguel Allende

Continuous high-resolution in vivo imaging reveals tumor-specific dissemination in an embryonic zebrafish xenograft model. Nandini Asokan, Stephan Daetwyler, Stefanie Nadine Bernas, Christopher Schmied, Steffen Volger, Katrin Lambert, Manja Wobus, Martin Wermke, Gerd Kempermann, Jan Huisken, Michael Brand, Martin Bornhaeuser

Mutations in C11ORF70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to outer and inner dynein arm defects. Inga M Höben, Rim Hjeij, Heike Olbrich, Gerard W Dougherty, Tabea Menchen, Isabella Aprea, Diana Frank, Petra Pennekamp, Bernd Dworniczak, Julia Wallmeier, Johanna Raidt, Kim G Nielsen, Maria C Philipsen, Francesca Santamaria, Laura Venditto, Israel Amirav, Freerk Prenzel, Kaman Wu, Miriam Schmidts, Niki T Loges, Heymut Omran

A phase separated organelle at the root of motile ciliopathy. Ryan Huizar, Chanjae Lee, Alexander Boulgakov, Amjad Horani, Fan Tu, Kevin Drew, Edward Marcotte, Steven Brody, John Wallingford

Phenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells. Maurizio Chioccioli, Luigi Feriani, Jurij Kotar, Preston E. Bratcher,  Pietro Cicuta

Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes. Michael S. Breen, Aliza P. Wingo, Nastassja Koen, Kirsten A. Donald, Heather J. Zar, Kerry J. Ressler, Joseph D. Buxbaum, Dan J. Stein

Developmental And Genetic Regulation Of The Human Cortex Transcriptome In Schizophrenia. Andrew E Jaffe, Richard E Straub, Joo Heon Shin, Ran Tao, Yuan Gao, Leonardo Collado Torres, Tony Kam-Thong, Hualin S Xi, Jie Quan, Qiang Chen, Carlo Colantuoni, William S Ulrich, Brady J Maher, Amy Deep-Soboslay, The BrainSeq Consortium, Alan Cross, Nicholas J Brandon, Jeffrey T Leek, Thomas M Hyde, Joel E Kleinman, Daniel R Weinberger

Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development. Laura M Huckins, Amanda Dobbyn, Douglas Ruderfer, Gabriel Hoffman, Weiqing Wang, Antonio F Pardinas, Veera M Rajagopal, Thomas D Als, Hoang Tan Hoang, Kiran Girdhar, James Boocock, Panagiotis Roussos, Menachem Fromer, Robin Kramer, Enrico Domenici, Eric Gamazon, Shaun Purcell, CommonMind Consortium, Schizophrenia Working Group of the Psychiatric Gen, iPSYCH-GEMS Schizophrenia Working Group, Ditte Demontis, Anders Borglum, James Walters, Michael O’Donovan, Patrick F Sullivan, Micahel Owen, Bernie Devlin, Solveig K Sieberts, Nancy Cox, Hae Kyung Im, Pamela Sklar, Eli Ayumi Stahl

Germ line aging and regional epigenetic instability: age prediction using human sperm DNA methylation signatures. Timothy G Jenkins, Kenneth I Aston, Douglas T Carrell

Aging and neurodegeneration are associated with increased mutations in single human neurons. Michael A Lodato, Rachel E Rodin, Craig L Bohrson, Michael E Coulter, Alison R Barton, Minseok Kwon, Maxwell A Sherman, Carl M Vitzhum, Lovelace J Luquette, Chandri Yandava, Pengwei Yang, Thomas W Chittenden, Nicole E Hatem, Steven C Ryu, Mollie B Woodworth, Peter J Park, Christopher A Walsh

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins. Yunzhang Wang, Robert Karlsson, Erik Lampa, Qian Zhang, Åsa K. Hedman, Malin Almgren, Catarina Almqvist, Allan F. McRae, Riccardo Marioni, Erik Ingelsson, Peter M. Visscher, Ian J. Deary, Lars Lind, Tiffany Morris, Stephan Beck, Nancy L. Pedersen, Sara Hägg

Identification of key pathways and metabolic fingerprints of longevity in C. elegans. Arwen Gao, Reuben Smith, Michel Van Weeghel, Rashmi Kamble, Riekelt Houtkooper

An essential post-developmental role for Lis1 in mice. Timothy J Hines, Xu Gao, Subhshri Sahu, Meghann M Lange, Jill R Turner, Jeffery L Twiss, Deanna S Smith

A urine-dependent human urothelial organoid offers a promising alternative to rodent models of infection. Harry Horsley, Dhanuson Dharmasena, James Malone-Lee, Jennifer L. Rohn

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC. Mathijs A. Sanders, Edward Chew, Christoffer Flensburg, Annelieke Zeilemaker, Sarah E. Miller, Adil al Hinai, Ashish Bajel, Bram Luiken, Melissa Rijken, Tamara Mclennan, Remco M. Hoogenboezem, François G. Kavelaars, Marnie E. Blewitt, Eric M. Bindels, Warren S. Alexander, Bob Löwenberg, Andrew W. Roberts, Peter J. M. Valk, Ian Majewski

An Essential Role for Argonaute 2 in EGFR-KRAS Signaling in Pancreatic Cancer Development. Sunita Shankar, Jean Tien, Ronald F Siebenaler, Vijaya L Dommeti, Sylvia Zelenka-Wang, Kristin M Juckette, Alice Xu, Malay Mody, Andrew Goodrum, Grace Tsaloff, Ingrid J Apel, Lisha Wang, Javed Siddiqui, Jiaqi Shi, Chandan Kumar-Sinha, Arul M Chinnaiyan

Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease. Jean C. Cruz Hernandez, Oliver Bracko, Calvin J. Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K. Vinarcsik, Iryna Ivasyk, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D. Beverly, Elizabeth Davenport, Yohan Davit, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B. Schaffer

PPARD regulation in gastric progenitor cells drives gastric tumorigenesis in mice. Xiangsheng Zuo, Yasunori Deguchi, Weiguo Xu, Daoyan Wei, Rui Tian, Weidong Chen, Micheline J. Moussalli, Yi Liu, Fei Mao, Min Xu, Yaying Yang, Shen Gao, Jonathan C. Jaoude, Fuyao Liu, Mihai Gagea, Russell Broaddus, Keping Xie, Imad Shureiqi

L-tyrosine supplementation is not therapeutic for skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy. Adriana M. Messineo, Charlotte Gineste, Tamar E. Sztal, Elyshia L McNamara, Christophe Vilmen, Augustin C. Ogier, Dorothee Hahne, David Bendahan, Nigel G. Laing, Robert J. Bryson-Richardson, Julien Gondin, Kristen J. Nowak

Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. David A. Knowles, Courtney K. Burrows, John D. Blischak, Kristen M. Patterson, Carole Ober, Jonathan K. Pritchard, Yoav Gilad

Endothelial Cell-Specific MCPIP Deletion Causes Endothelial Dysfunction and Impairs Post-ischemic Angiogenesis in Vivo. Jianli Niu, Nidhi Kapoor, Jian Liang, Zhuqing Jin, Edilu Becerra, Pappachan E. Kolattukudy

PKD2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. Xiaowen Liu, Thuy Vien, Jingjing Duan, Shu-Hsien Sheu, Paul G. DeCaen, David E. Clapham

Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids. Sabrina A. Rocco, Lada Koneva, Lauren Y. M. Middleton, Tasha Thong, Sumeet Solanki, Sarah Karram, Kowit Nambunmee, Craig Harris, Laura S. Rozek, Maureen A. Sartor, Yatrik M. Shah, Justin Colacino

Genomic Locus Modulating Corneal Thickness in the Mouse Identifies POU6F2 as a Potential Risk of Developing Glaucoma. Rebecca King, Felix L. Struebing, Ying Li, Jiaxing Wang, Allison Ashley Koch, Jessica Cooke Bailey, Puya Gharahkhan, Stuart MacGregor, R. Rand Allingham, Michael A. Hauser, Janey L. Wiggs, Eldon E. Geisert

Clonal analysis of newborn hippocampal dentate granule cell proliferation and development in temporal lobe epilepsy. Shatrunjai P. Singh, Candi L. LaSarge, Amen An, John J. McAuliffe, Steve C. Danzer

Evo-devo & evo

Hox genes pattern the primary body axis of an anthozoan cnidarian prior to gastrulation. Timothy Q. DuBuc, Thomas B. Stephenson, Amber N. Rock, Mark Q. Martindale

Gene regulatory network architecture in different developmental contexts influences the genetic basis of morphological evolution. Sebastian Kittelmann, Alexandra D. Buffry, Isabel Almudi, Marianne Yoth, Gonzalo Sabaris, Franziska A. Franke, Juan Pablo Couso, Maria D. S. Nunes, Nicolas Frankel, Jose Luis Gomez-Skarmeta, Jose Pueyo-Marques, Saad Arif, Alistair P. McGregor

Duplication and divergence of Sox genes in spiders. Christian L. B. Paese, Daniel J. Leite, Anna Schoenauer, Alistair P. McGregor, Steven Russell

Pervasive correlated evolution in gene expression shapes cell type transcriptomes. Cong Liang, Jacob M. Musser, Alison Cloutier, Richard Prum, Gunter Wagner

How morphological development can guide evolution. Sam Kriegman, Nick Cheney, Josh Bongard

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages. Dennis Kostka, Alisha K. Holloway, Katherine Pollard

Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex. Marta Florio, Michael Heide, Holger Brandl, Anneline Pinson, Sylke Winkler, Pauline Wimberger, Wieland B. Huttner, Michael Hiller

Developmental constraints on genome evolution in four bilaterian model species. Jialin Liu, Marc Robinson-Rechavi

The role of chromosomal inversions in speciation. Zachary Fuller, Christopher Leonard, Randee Young, Stephen Schaeffer, Nitin Phadnis

Gene regulatory network rewiring by an adaptively evolving microRNA cluster in Drosophila. Yang Lyu, Zhongqi Liufu, Juan Xiao, Yuxin Chen, Chung-I Wu, Tian Tang

Rapid evolution of gained essential developmental functions of a young gene via interactions with other essential genes. Yuh Chwen G Lee, Iuri M Ventura, Gavin R Rice, Don-Yuan Chen, Manyuan Long

The asexual genome of Drosophila. Stephan Schiffels, Ville Mustonen, Michael Lässig

Improved genome assembly and annotation for the rock pigeon (Columba livia). Carson Holt, Michael Campbell, David Keays, Nathaniel Edelman, Aurelie Kapusta, Emily Maclary, Eric Domyan, Alexander Suh, Wesley Warrenb, Mark Yandell, Thomas Gilbert, Michael D. Shapiro

Hemimetabolous genomes reveal molecular basis of termite eusociality. Mark C. Harrison, Evelien Jongepier, Hugh M. Robertson, Nicolas Arning, Tristan Bitard-Feildel, Hsu Chao, Christopher P. Childers, Huyen Dinh, Harshavardhan Doddapaneni, Shannon Dugan, Johannes Gowin, Carolin Greiner, Yi Han, Haofu Hu, Daniel S. T. Hughes, Ann-Kathrin Huylmans, Carsten Kemena, Lukas P. M. Kremer, Sandra L. Lee, Alberto Lopez-Ezquerra, Ludovic Mallet, Jose M. Monroy-Kuhn, Annabell Moser, Shwetha C. Murali, Donna M. Muzny, Saria Otani, Maria-Dolors Piulachs, Monica Poelchau, Jiaxin Qu, Florentine Schaub, Ayako Wada-Katsumata, Kim C. Worley, Qiaolin Xie, Guillem Ylla, Michael Poulsen, Richard A. Gibbs, Coby Schal, Stephen Richards, Xavier Belles, Judith Korb, Erich Bornberg-Bauer

Insights into platypus population structure and history from whole-genome sequencing. Hilary C Martin, Elizabeth M Batty, Julie Hussin, Portia Westall, Tasman Daish, Stephen Kolomyjec, Paolo Piazza, Rory Bowden, Margaret Hawkins, Tom Grant, Craig Moritz, Frank Grutzner, Jaime Gongora, Peter Donnelly

Reduction in major transcription factor binding domain families during the evolution of the avian lineage. Allie M. Graham, Jason S. Presnell

Host shifts result in parallel genetic changes when viruses adapt to closely related species. Ben Longdon, Jonathan P Day, Joel M Alves, Sophia CL Smith, Thomas M Houslay, John E McGonigle, Lucia Tagliaferri, Francis M Jiggins

Overlooked polyploidies in lycophytes generalize their roles during the evolution of vascular plants. Jinpeng Wang, Jigao Yu, Pengchuan Sun, Chao Li, Xiaoming Song, Tianyu Lei, Yuxian Li, Jiaqing Yuan, Sangrong Sun, Hongling Ding, Xueqian Duan, Shaoqi Shen, Yanshuang Shen, Jing Li, Fanbo Meng, Yangqin Xie, Jianyu Wang, Yue Hou, Jin Zhang, Xianchun Zhang, Xiyin Wang

A primitive starfish ancestor from the Early Ordovician of Morocco reveals the origin of crown group Echinodermata. Aaron W. Hunter, Javier Ortega-Hernandez

Russian Doll Genes and Complex Chromosome Rearrangements in Oxytricha trifallax. Jasper Braun, Lukas Nabergall, Rafik Neme, Laura F Landweber, Masahico Saito, Natasha Jonoska

Nearly Neutral Evolution Across the Drosophila melanogaster Genome. David Castellano, Jennifer James, Adam Eyre-Walker

Cell biology

Formation and disassembly of a contractile actomyosin network mediates content release from large secretory vesicles. Dagan Segal, Assaf Zaritsky, Eyal D. Schejter, Ben Zion Shilo

Variation in traction forces during cell cycle progression. Benoit Vianay, Fabrice Senger, Simon Alamos, Maya Anjur-Dietrich, Elizabeth Bearce, Bevan Cheeseman, Lisa Lee, Manuel Thery

Cell size control driven by the circadian clock and environment in cyanobacteria. Bruno M. C. Martins, Amy K. Tooke, Philipp Thomas, James C. W. Locke

RodZ promotes MreB polymer formation and curvature localization to determine the cylindrical uniformity of E. coli shape. Randy M Morgenstein, Benjamin P Bratton, Joshua W Shaevitz, Zemer Gitai

Giant flagellins form thick flagellar filaments in two species of marine Gammaproteobacteria. Nicholas Maitland Thomson, Josie L Ferreira, Teige R Matthews-Palmer, Morgan Beeby, Mark J Pallen

Uncoupling Intraflagellar Transport and Primary Cilia Formation Demonstrates Deep Integration of IFT in Hedgehog Signaling. Thibaut Eguether, Fabrice P Cordelieres, Gregory J Pazour

CDC20B is required for deuterosome-mediated centriole production in multiciliated cells. Diego R. Revinski, Laure-Emmanuelle Zaragosi, Camille Boutin, Sandra Ruiz-Garcia, Marie Deprez, Olivier Rosnet, Virginie Thome, Olivier Mercey, Agnes Paquet, Nicolas Pons, Brice Marcet, Laurent Kodjabachian, Pascal Barbry

Structural centrosome aberrations promote non-cell-autonomous invasiveness. Olivier Ganier, Dominik Schnerch, Philipp Oertle, Roderick Y. H. Lim, Marija Plodinec, Erich A. Nigg

A robust and tunable mitotic oscillator in artificial cells. Ye Guan, Zhengda Li, Shiyuan Wang, Patrick M. Barnes, Xuwen Liu, Haotian Xu, Minjun Jin, Allen P. Liu, Qiong Yang

Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore. Xun Bao, Christos Spanos, Tomoko Kojidani, Eric Lynch, Juri Rappsilber, Yasushi Hiraoka, Tokuko Haraguchi, Kenneth Sawin

Endocytosis caused by liquid-liquid phase separation of proteins. Louis-Philippe Bergeron-Sandoval, Hossein Khadivi Heris, Adam G. Hendricks, Allen J. Ehrlicher, Paul Francois, Rohit V. Pappu, Stephen W. Michnick

Systematic analysis of the molecular architecture of endocytosis reveals a nanoscale actin nucleation template that drives efficient vesicle formation. Markus Mund, Johannes Albertus van der Beek, Joran Deschamps, Serge Dmitrieff, Jooske Louise Monster, Andrea Picco, Francois Nedelec, Marko Kaksonen, Jonas Ries

The contributions of the actin machinery to endocytic membrane bending and vesicle formation. Andrea Picco, Wanda Kukulski, Hetty E. Manenschijn, Tanja Specht, John A. G. Briggs, Marko Kaksonen

CYRI (FAM49) proteins are local inhibitors of Scar/WAVE induced lamellipodia that bind directly to active Rac1. Loic Fort, Jose Batista, Peter A Thomason, Heather J Spence, Jennifer Greaves, Kirsty J Martin, Kurt I Anderson, Peter Brown, Sergio Lilla, Matthwe P Neilson, Petra Tafelmeyer, Sara Zanivan, Shehab Ismail, Nicholas C.O. Tomkinson, Luke H Chamberlain, Robert H Insall, Laura M Machesky

Dynein dynamics at the microtubule plus-ends and cortex during division in the C. elegans zygote. Ruddi Rodriguez-Garcia, Laurent Chesneau, Sylvain Pastezeur, Julien Roul, Marc Tramier, Jacques Pecreaux

The tumor suppressor APC is an attenuator of spindle-pulling forces during C. elegans asymmetric cell division. Kenji Sugioka, Lars-Eric Fielmich, Kota Mizumoto, Bruce Bowerman, Sander van den Heuvel, Akatsuki Kimura, Hitoshi Sawa

Dissecting single cell molecular spatiotemporal mobility and clustering at Focal Adhesions in polarised cells by fluorescence fluctuation spectroscopy methods. Jorge Bernardino de la Serna, Esther Garcia

Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel. Bo Yang, Haguy Wolfenson, Naotaka Nakazawa, Shuaimin Liu, Junqiang Hu, Michael Sheetz

Modelling

Model reduction permits Turing instability analysis of arbitrary reaction-diffusion models. Stephen Smith, Neil Dalchau

The phenomenon of growing surface interference explains the rosette pattern of jaguar. Michäel Dougoud, Christian Mazza, Beat Schwaller, Laszlo Pecze

Dynamic gradient scaling as a critical point of growth control. Daniel Aguilar Hidalgo, Steffen Werner, Ortrud Wartlick, Marcos González-Gaitán, Benjamin Friedrich, Frank Jülicher

Temporal precision of regulated gene expression. Shivam Gupta, Julien Varennes, Hendrik C. Korswagen, Andrew Mugler

A biophysical model explains the spontaneous bursting behavior in the developing retina. Dora Karvouniari, Lionel Gil, Olivier Marre, Serge Picaud, Bruno Cessac

An efficient gene regulatory network inference algorithm for early Drosophila melanogaster embryogenesis. Hirotaka Matsumoto, Hisanori Kiryu, Yasuhiro Kojima, Suguru Yaginuma, Itoshi Nikaido

Turbulent dynamics of epithelial cell cultures. C. Blanch-Mercader, V. Yashunsky, S. Garcia, G. Duclos, L. Giomi, P. Silberzan

Mechanical characterisation of disordered and anisotropic cellular monolayers. Alexander Nestor-Bergmann, Emma Johns, Sarah Woolner, Oliver E. Jensen

Do cells sense time by number of divisions? Zeev Schuss, Kimsy Tor, David Holcman

Euplotid: A quantized geometric model of the eukaryotic cell. Diego Borges-Rivera

Noise-driven Cell Differentiation and the Emergence of Organization. Hadiseh Safdari, Ata Kalirad, Cristian Picioreanu, Rouzbeh Tusserkani, Mehdi Sadeghi

A biophysical dynamic module for the polarisation of auxin efflux carriers PIN-FORMED (PIN). Valeria Hernandez-Hernandez, Rafael A. Barrio, Mariana Benitez, Naomi Nakayama, Jose Roberto Romero-Arias, Carlos Villarreal

Discrete and continuum approximations for collective cell migration in a scratch assay with cell size dynamics. Oleksii M Matsiaka, Catherine Penington, Ruth E Baker, Matthew Simpson

Shaping Epigenetic Memory via Genomic Bookmarking. Davide Michieletto, Michael Chiang, Davide Coli, Argyris Papantonis, Enzo Orlandini, Peter R. Cook, Davide Marenduzzo

Subtle alteration in microRNA dynamics accounts for differential nature of cellular proliferation. Dola Sengupta, Vinodhini Govindaraj, Sandip Kar

Mathematics at the eve of a historic transition in biology. Guo-Wei Wei

Tools & resources

| Imaging etc.

EpiGraph: an open-source platform to quantify epithelial organization. Pablo Vicente-Munuera, Pedro Gomez-Galvez, Antonio Tagua, Marta Letran, Yanlan Mao, Luis M. Escudero

An adaptable chromosome preparation methodology for use in invertebrate research organisms. Longhua Guo, Alice Accorsi, Shuonan He, Carlos Guerrero-Hernández, Shamilene Sivagnanam, Sean McKinney, Matthew Gibson, Alejandro Sánchez Alvarado

Combined flow cytometry and high throughput image analysis for the study of essential genes in Caenorhabditis elegans. Blanca Hernando-Rodríguez, Annmary Paul Erinjeri, María Jesús Rodríguez-Palero, Val Millar, Sara González-Hernández, María Olmedo, Bettina Schulze, Ralf Baumeister, Manuel J. Muñoz, Peter Askjaer, Marta Artal-Sanz

A method to keep the excitation light sheet in focus in selective plane illumination microscopy. Liang Gao

Topography and refractometry of sperm cells using SLIM. Lina Liu, Mikhail E Kandel, Marcello Rubessa, Sierra Schreiber, Mathew Wheeler, Gabriel Popescu

Simultaneously measuring image features and resolution in live-cell STED images. Andrew E. S. Barentine, Lena K. Schroeder, Michael Graff, David Baddeley, Joerg Bewersdorf

3D label-free imaging and analysis of Pinus pollen grains using optical diffraction tomography. Geon Kim, SangYun Lee, Seungwoo Shin, YongKeun Park

Three dimensional cross-modal image inference: label-free methods for subcellular structure prediction. Chek Ounkomol, Daniel A. Fernandes, Sharmishtaa Seshamani, Mary M. Maleckar, Forrest Collman, Gregory R. Johnson

Optical crosstalk in SPAD arrays for high-throughput single-molecule fluorescence spectroscopy. Antonino Ingargiola, Maya Segal, Angelo Gulinatti, Ivan Rech, Ivan Labanca, Piera Maccagnani, Massimo Ghioni, Shimon Weiss, Xavier Michalet

Recording neural activity in unrestrained animals with 3D tracking two photon microscopy. Doycho Karagyozov, Mirna Mihovilovic Skanata, Amanda Lesar, Marc Gershow

A genetically encoded Ca2+ indicator based on circularly permutated sea anemone red fluorescent protein. Yi Shen, Hod Dana, Ahmed S. Abdelfattah, Ronak Patel, Jamien Shea, Rosana S. Molina, Bijal Rawal, Vladimir Rancic, Yu-Fen Chang, Lanshi Wu, Yingche Chen, Yong Qian, Matthew D. Wiens, Nathan Hambleton, Klaus Ballanyi, Thomas E. Hughes, Mikhail Drobizhev, Douglas S. Kim, Minoru Koyama, Eric R. Schreiter, Robert E. Campbell

A FRET based biosensor for measuring Gα13 activation in single cells. Marieke Mastop, Nathalie R. Reinhard, Cristiane R. Zuconelli, Fenna Terwey, Theodorus W. J. Gadella Sr., Jakobus van Unen, Merel J. W. Adjobo-Hermans, Joachim Goedhart

Understanding boundary effects and confocal optics enables quantitative FRAP analysis in the confined geometries of animal, plant, and fungal cells. James L Kingsley, Jeffrey P Bibeau, Iman Mousavi, Cem Unsal, Zhilu Chen, Xinming Huang, Luis Vidali, Erkan Tuzel

Multidimensional quantitative analysis of mRNA expression within intact vertebrate embryos. Vikas Trivedi, Harry M. T. Choi, Scott E. Fraser, Niles A. Pierce

Single-molecule fluorescent amplification of RNA using clampFISH probes. Sara H Rouhanifard, Margaret Dunagin, Ian A Mellis, Sareh Bayatpour, Orsolya Symmons, Allison Cote, Arjun Raj

An optimized pipeline for parallel image-based quantification of gene expression and genotyping after in situ hybridization. Tomasz Dobrzycki, Monika Krecsmarik, Florian Bonkhofer, Roger K Patient, Rui Monteiro

Quantitative methods to investigate the 4D dynamics of heterochromatic repair sites in Drosophila cells. Christopher P Caridi, Laetitia Delabaere, Harianto Tjong, Hannah Hopp, Devika Das, Frank Alber, Irene Chiolo

In vivo multiphoton fluorescence imaging with polymer dots. Ahmed M Hassan, Xu Wu, Jeremy W Jarrett, Shihan Xu, David R Miller, Jiangbo Yu, Evan P Perillo, Yen-Liang Liu, Daniel T Chiu, Hsin-Chih Yeh, Andrew K Dunn

Eukaryotically expressed encapsulins as orthogonal compartments for multiscale molecular imaging. Felix Sigmund, Christoph Massner, Philipp Erdmann, Anja Stelzl, Hannes Rolbieski, Helmut Fuchs, Martin Hrabe de Angelis, Mitul Desai, Sarah Bricault, Alan Jasanoff, Vasilis Ntziachristos, Juergen Plitzko, Gil Gregor Westmeyer

Brillouin microscopy, what is it really measuring? Pei-Jung Wu, Irina Kabakova, Jeffrey Ruberti, Joseph M. Sherwood, Iain E. Dunlop, Carl Paterson, Peter Török, Darryl R. Overby

REASSESSING THE REVOLUTIONS RESOLUTIONS. Marin van Heel, Michael Schatz

Simultaneous Determination of Protein Structure and Dynamics Using Cryo-Electron Microscopy. Massimiliano Bonomi, Riccardo Pellarin, Michele Vendruscolo

ShuTu: Open-Source Software for Efficient and Accurate Reconstruction of Dendritic Morphology. Dezhe Z. Jin, Ting Zhao, David Hunt, Rachel Pearcy, Ching-Lung Hsu, Nelson Spruston

Automated 3D Neuron Tracing with Precise Branch Erasing and Confidence Controlled Back-Tracking. Siqi Liu, Donghao Zhang, Yang Song, Hanchuan Peng, Weidong Cai

MICCS: A Fully Programmable Multipurpose Integrated Cell Culture System. Timothy Kassis, Paola M. Perez, Chloe J. W. Yang, Luis R. Soenksen, David L. Trumper, Linda G. Griffith

Visual Representation of Experimental Protocols. James Scott-Brown, Antonis Papachristodoulou

Protein structures as shapes: Analysing protein structure variation using geometric morphometrics. Jose Sergio Hleap, Christian Blouin

Which line to follow? The utility of different line-fitting methods to capture the mechanism of morphological scaling. Alexander W. Shingleton

A Cautionary Tail: Changes in Integrin Behavior with Labeling. Catherine G. Galbraith, Michael W. Davidson, James A. Galbraith

Exploring biological networks in 3D, stereoscopic 3D and immersive 3D with iCAVE. Selim Kalayci, Zeynep H. Gumus

Quantitative imaging of chromatin decompaction in living cells. Elisa Dultz, Roberta Mancini, Guido Polles, Pascal Vallotton, Frank Alber, Karsten Weis

| Genome tools

CRISPys: Optimal sgRNA design for editing multiple members of a gene family using the CRISPR system. Gal Hyams, Shiran Abadi, Adi Avni, Eran Halperin, Eilon Shani, Itay Mayrose

Potential high-frequency off-target mutagenesis induced by CRISPR/Cas9 in Arabidopsis and its prevention. Qiang Zhang, Hui-Li Xing, Zhi-Ping Wang, Hai-Yan Zhang, Fang Yang, Xue-Chen Wang, Qi-Jun Chen

CRISPR-Cas12a target binding unleashes single-stranded DNase activity. Janice S Chen, Enbo Ma, Lucas B Harrington, Xinran Tian, Jennifer A Doudna

SgTiler: a fast method to design tiling sgRNAs for CRISPR/Cas9 mediated screening. Musaddeque Ahmed, Housheng Hansen He

Easy quantification of template-directed CRISPR/Cas9 editing. Eva Karina Brinkman, Arne Nedergaard Kousholt, Tim Harmsen, Christ Leemans, Tao Chen, Jos Jonkers, Bas van Steensel

Covalent linkage of the DNA repair template to the CRISPR/Cas9 complex enhances homology-directed repair. Natasa Savic, Femke Ringnalda, Katja Bargsten, Yizhou Li, Christian Berk, Jonathan Hall, Dario Neri, Martin Jinek, Gerald Schwank

Rapid, modular, and cost-effective generation of donor DNA constructs for CRISPR-based gene knock-in. Yi-Jiun Chen, Weikang Wang, Xiao-Jiun Tian, Daniel E. Lefever, David A. Taft, Jianhua Xing

Transgenic mouse lines expressing the 3xFLAG-dCas9 protein for enChIP analysis. Toshitsugu Fujita, Fusako Kitaura, Asami Oji, Naoki Tanigawa, Miyuki Yuno, Masahito Ikawa, Ichiro Taniuchi, Hodaka Fujii

A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality. Tanya L Daigle, Linda Madisen, Travis A Hage, Matthew T Valley, Ulf Knoblich, Rylan S Larsen, Marc M Takeno, Lawrence Huang, Hong Gu, Rachael Larsen, Maya Mills, Alice Bosma-Moody, La’Akea Siverts, Miranda Walker, Lucas T Graybuck, Zizhen Yao, Olivia Fong, Emma Garren, Garreck Lenz, Mariya Chavarha, Julie Pendergraft, James Harrington, Karla E Hirokawa, Julie A Harris, Medea McGraw, Douglas R Ollerenshaw, Kimberly Smith, Baker A Baker, Jonathan T Ting, Susan M Sunkin, Jerome Lecoq, Michael Z Lin, Edward S Boyden, Gabe J Murphy, Nuno da Costa, Jack Waters, Lu Li, Bosiljka Tasic, Hongkui Zeng

A versatile genetic tool for post-translational control of gene expression in Drosophila melanogaster. Sachin Sethi, Jing W. Wang

Saturating Single-Cell Datasets. Aparna Bhaduri, Tomasz J. Nowakowski, Alex A. Pollen, Arnold R. Kriegstein

Comparison of whole-genome bisulfite sequencing library preparation strategies identifies sources of biases affecting DNA methylation data. Nelly Olova, Felix Krueger, Simon Andrews, David Oxley, Rebecca V Berrens, Miguel R Branco, Wolf Reik

Rapid high-resolution measurement of DNA replication timing by droplet digital PCR. Dzmitry G. Batrakou, Emma D. Heron, Conrad A. Nieduszynski

Improving Gene Regulatory Network Inference by Incorporating Rates of Transcriptional Change.Jigar Desai, Ryan C. Sartor, Lovely Mae Lawas, Krishna S. V. Jagadish, Colleen J. Doherty

Removing unwanted variation between samples in Hi-C experiments. Kipper Fletez-Brant, Yunjiang Qiu, David U Gorkin, Ming Hu, Kasper D Hansen

Binless normalization of Hi-C data provides significant interaction and difference detection independently of resolution. Yannick G. Spill, David Castillo, Marc A. Marti-Renom

Leveraging multiple transcriptome assembly methods for improved gene structure annotation. Luca Venturini, Shabhonam Caim, Gemy Kaithakottil, Daniel Lee Mapleson, David Swarbreck

Spliceosome profiling visualizes the operations of a dynamic RNP in vivo at nucleotide resolution. Jordan Burke, Adam Longhurst, Daria Merkurjev, Jade Sales-Lee, Beiduo Rao, James Moresco, John Yates III, Jingyi Jessica Li, Hiten D Madhani

Transcriptome-wide analysis of the functional intronome using spliceosome profiling. Weijun Chen, Jill Moore, Hakan Ozadam, Hennady P Shulha, Nicholas Rhind, Zhiping Weng, Melissa J. Moore

TF2Network: predicting transcription factor regulators and gene regulatory networks in Arabidopsis using publicly available binding site information. Shubhada R. Kulkarni, Dries Vaneechoutte, Jan Van de Velde, Klaas Vandepoele

FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data. Josip Stefan Herman, Sagar Sagar, Dominic Grun

Cross-Site Comparison of Ribosomal Depletion Kits for Illumina RNAseq Library Construction. Zachary T Herbert, Jamie P Kershner, Vincent L Butty, Jyothi Thimmapuram, Sulbha Choudhari, Yuriy O Alekseyev, Jun Fan, Jessica W Podnar, Edward Wilcox, Jenny Gipson, Allison Gillaspy, Kristen Jepsen, Sandra Splinter BonDurant, Krystalynne Morris, Maura Berkeley, Ashley LeClerc, Stephen D. Simpson, Gary Sommerville, Leslie Grimmett, Marie Adams, Stuart S. Levine

An interlaboratory study of complex variant detection. Stephen E Lincoln, Justin M Zook, Shimul Chowdhury, Shazia Mahamdallie, Andrew Fellowes, Eric W Klee, Rebecca Truty, Catherine Huang, Farol L Tomson, Megan H Cleveland, Peter M Vallone, Yan Ding, Sheila Seal, Wasanthi DeSilva, Russell K Garlick, Marc Salit, Nazneen Rahman, Stephen F Kingsmore, Swaroop Aradhya, Robert L Nussbaum, Matthew J Ferber, Brian H Shirts

MEGAN-LR: New algorithms allow accurate binning and easy interactive exploration of metagenomic long reads and contigs. Daniel Huson, Benjamin Albrecht, Caner Bagci, Irina Bessarab, Anna Gorska, Dino Jolic, Rohan B.H. Williams

CREAM: Clustering of genomic REgions Analysis Method. Seyed Ali Madani Tonekaboni, Parisa Mazrooei, Victor Kofia, Benjamin Haibe-Kains, Mathieu Lupien

The fractured landscape of RNA-seq alignment: The default in our STARs. Sara Ballouz, Alexander Dobin, Thomas R Gingeras, Jesse Gillis

miRAW: A deep learning approach to predict miRNA targets by analyzing whole miRNA transcripts. Albert Pla Planas, Xiangfu Zhong, Simon Rayner

Classifying cells with Scasat – a tool to analyse single-cell ATAC-seq. Syed Murtuza Baker, Connor Rogerson, Andrew Hayes, Andrew D. Sharrocks, Magnus Rattray

scmap – A tool for unsupervised projection of single cell RNA-seq data. Vladimir Yu. Kiselev, Andrew Yiu, Martin Hemberg

Expressed Exome Capture Sequencing (EecSeq): a method for cost-effective exome sequencing for all organisms with or without genomic resources. Jonathan B Puritz, Kathleen E Lotterhos

Tn5Prime, a Tn5 based 5′ Capture Method for Single Cell RNA-seq. Charles Cole, Ashley Byrne, Anna E. Beaudin, E. Camilla Forsberg, Christopher Vollmers

Mantis: A Fast, Small, and Exact Large-Scale Sequence Search Index. Prashant Pandey, Fatemeh Almodaresi, Michael A. Bender, Michael Ferdman, Rob Johnson, Rob Patro

SpatialDE – Identification of spatially variable genes. Valentine Svensson, Sarah A. Teichmann, Oliver Stegle

Technology-independent estimation of cell type composition using differentially methylated regions. Stephanie C. Hicks, Rafael A. Irizarry

Revisiting criteria for plant miRNA annotation in the era of big data. Michael J. Axtell, Blake C. Meyers

OMGene: Mutual improvement of gene models through optimisation of evolutionary conservation. Michael Dunne, Steven Kelly

Research practice

Community-driven data analysis training for biology. Bérénice Batut, Saskia Hiltemann, Andrea Bagnacani, Dannon Baker, Vivek Bhardwaj, Clemens Blank, Anthony Bretaudeau, Loraine Guéguen, Martin Čech, John Chilton, Dave Clements, Olivia Doppelt-Azeroual, Anika Erxleben, Mallory Freeberg, Simon Gladman, Youri Hoogstrate, Hans-Rudolf Hotz, Torsten Houwaart, Pratik Jagtap, Delphine Lariviere, Gildas Le Corguillé, Thomas Manke, Fabien Mareuil, Fidel Ramírez, Devon Ryan, Florian Sigloch, Nicola Soranzo, Joachim Wolff, Pavankumar Videm, Markus Wolfien, Aisanjiang Wubuli, Dilmurat Yusuf, Rolf Backofen, Anton Nekrutenko, Björn Grüning

How Changes in Common Practice Can Improve the Quality of Biomedical Science. Matthias Steinfath, Silvia Vogl, Norman Violet, Franziska Schwarz, Hans Mielke, Thomas Selhorst, Matthias Greiner, Gilbert Schoenfelder

The impact factor fallacy. Frieder Michel Paulus, Nicole Cruz, Soeren Krach

Explanation implies causation? Leslie Myint, Jeffrey T. Leek, Leah R. Jager

Assessing value of biomedical digital repositories. Chun-Nan Hsu​, Anita Bandrowski, Jeffrey S. Grethe, Maryann E. Martone

Manipulating the alpha level cannot cure significance testing – comments on “Redefine statistical significance”. Trafimow D, Amrhein V, Areshenkoff CN, Barrera-Causil C, Beh EJ, Bilgiç Y, Bono R, Bradley MT, Briggs WM, Cepeda-Freyre HA, Chaigneau SE, Ciocca DR, Carlos Correa J, Cousineau D, de Boer MR, Dhar SS, Dolgov I, Gómez-Benito J, Grendar M, Grice J, Guerrero-Gimenez ME, Gutiérrez A, Huedo-Medina TB, Jaffe K, Janyan A, Karimnezhad A, Korner-Nievergelt F, Kosugi K, Lachmair M, Ledesma R, Limongi R, Liuzza MT, Lombardo R, Marks M, Meinlschmidt G, Nalborczyk L, Nguyen HT, Ospina R, Perezgonzalez JD, Pfister R, Rahona JJ, Rodríguez-Medina DA, Romão X, Ruiz-Fernández S, Suarez I, Tegethoff M, Tejo M, van de Schoot R, Vankov I, Velasco-Forero S, Wang T, Yamada Y, Zoppino FC, Marmolejo-Ramos F.

Key steps to avoiding artistry with significance tests. C Patrick Doncaster, Thomas H G Ezard

If funders and libraries subscribed to open access: The case of eLife, PLOS, and BioOne. Willinsky J, Rusk M.

Oxford Nanopore sequencing in a research-based undergraduate course. Yi Zeng, Christopher Herbert Martin

Why not…

Dietary and behavioral inferences from dental pathology and non-masticatory wear on dentitions from a British medieval town. Ian Towle, Carole Davenport, Joel Irish, Isabelle De Groote

Cobwebbing in the city: urbanization-driven changes in web-building are decoupled from body size in an orb-web spider. Maxime Dahirel, Maarten De Cock, Pieter Vantieghem, Dries Bonte

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A 3-year PhD fellowship in evolutionary developmental biology and genomics is available in the lab of Michalis Averof, at the Institut de Génomique Fonctionnelle de Lyon (IGFL) in France. The fellowship is funded by the Marie Curie ITN programme EvoCELL.

Some animals have the ability to regenerate parts of their body (limbs, tail, internal organs) after severe injury. However the molecular and cellular mechanisms underlying the regeneration of such complex organs are still poorly understood. The project will investigate cell differentiation during leg regeneration in the crustacean ​Parhyale hawaiensis, an emerging model for limb regeneration. The PhD fellow will determine the spectrum of cell types present in Parhyale limbs, their molecular profiles, and whether that diversity of cell types is fully restored after regeneration. In collaboration with other teams of the EvoCELL network, s/he will compare the transcriptional profiles of diverse cells types across phyla, in an effort to identify the evolutionary origins and conserved molecular signatures of progenitor cells.

The student will be trained in various technologies to analyze limb regeneration in Parhyale and compare it to regeneration in other species. S/he will use single-cell transcriptomics to establish the exhaustive repertoire of cell types prior to, during and after regeneration. S/he will participate in all steps of the experiment: dissociate limb cells, prepare libraries and computationally analyze the data. The fellow will also be trained in transgenesis, confocal microscopy and in situ hybridization in order to validate the identity of the detected cell populations and use markers to follow the fate of those cells during regeneration. This work will involve short periods of training/research in the laboratories of other EvoCELL partners and collaborators, and participation in yearly meetings and practical courses organized by the network, to take full advantage of the wide range of expertise available in EvoCELL.

The host lab (https://averof-lab.org) is based in the IGFL – an institute co-founded by the École Normale Supérieure de Lyon and the CNRS, whose scientific focus lies at the interface of developmental biology, functional genomics and evolution (http://igfl.ens-lyon.fr/). The lab’s working language is English. The fellow will be co-supervised by Michalis Averof and Mathilde Paris.

Applicants should have a Masters degree or equivalent (e.g. a 5-year university degree) to be eligible to embark on a PhD at the École Normale Supérieure de Lyon. To be eligible for the fellowship, candidates must be within the first four years of their research career and not hold a doctoral degree. Candidates of all nationalities may apply, but they must not have resided or carried out their main activity (work, studies, etc.) in France for more than 12 months in the 3 years immediately prior to their appointment (short stays such as holidays or compulsory national service are not taken into account).

The suggested starting date for the PhD is October 1, 2018.

Applicants should send a short letter of interest and CV to michalis.averof@ens-lyon.fr, and ask two referees to send recommendation letters to the same electronic address. The closing date for applications is February 2, 2018.

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Alzu’bi A, Lindsay SJ, Harkin LF, McIntyre J, Lisgo SN, Clowry GJ (2017) The transcription factors COUP-TFI and COUP-TFII have distinct roles in arealisation and GABAergic interneuron specification in the early human fetal telencephalon. Cerebral Cortex 27: 4677-4690.

One author’s perspective on the origins of this study (Gavin Clowry)

For me the origins of this research paper stretch back nearly twenty years. I was part of a research group, led by the paediatric neurologist Professor Janet Eyre, studying the neurobiology of cerebral palsy including neurophysiological studies on infants and children. A little boy with hemiplegia generated some remarkable results. He was unusual in that he had suffered a brain lesion relatively early in development compared to most CP sufferers, around mid-gestation, resulting in destruction of the sensorimotor cortex unilaterally. Transcranial magnetic stimulation, coupled with electromyographic recording, showed that muscles contralateral to the lesion were strongly responsive to stimulation of the ipsilateral motor cortex, not unusual in hemiplegics. What was unusual, though, was the strong response of the same muscles to stimulation of the intact contralateral occipital cortex. Ten more years of experiments and imaging were required to confirm these observations [1] but it was shown that in response to the lesion, visual cortex had acquired or maintained projections to motor centres in the spinal cord (Figure 1).

This set us speculating on the nature and plasticity of the protomap in human. Around this time strong evidence was being presented in favour of the protomap hypothesis originally proposed by Pasko Rakic [2]. The hypothesis stated that the organisation of the cerebral cortex into functional areas is determined by the co-ordinated and compartmented expression of genes in time and space at the earliest stages of its development, prior to its connection with the sensory input that could drive its maturation. Experiments in mice (Figure 2) [3, 4] were showing that altered gradients of transcription factor expression across the early cortex in mutant and transgenic mice led to an altered functional map for primary cortical areas. But does all this hold true for human development? For our next programme of research we teamed up with Prof Susan Lindsay and the Human Developmental Biology Resource to explore gene expression in the early stages of human cortex development especially to look for evidence for a human protomap.

Our first success was to show that the transcription factors PAX6 and EMX2 form counter-gradients across the human cortex, just as they do in mouse, but only at the very earliest stages of cortical plate formation (Figure 3) [6]. Unlike in mouse, where expression is confined to progenitor cells, EMX2 was found to be expressed in a gradient in the post-mitotic neurons of the cortical plate as well.  We also found arealised expression for other genes, by histological techniques, from quantitative measurements of mRNA expression, and in fetal cells cultured from different cortical regions [7, 8]. For instance, the layer V specific transcription factor CTIP2, along with transmembrane signalling molecules and corticospinal tract markers ROBO1 and SRGAP1, are more highly expressed in the frontal cortex between 9-12 PCW which might represent the predominance of corticofugal projection neurons in frontal sensorimotor areas.

However the crucial question is whether such a developmental scheme observed in rodents is sufficient to produce all the extra areas of specialised association cortex, along with the vastly increased interconnectivity between these areas, seen in primates [9]? We believe our latest study may shed some light on this question [10]. We studied expression patterns of the arealising transcription factors COUP-TFI, COUP-TFII and SP8. What was noticeable in humans was that SP8 and COUP-TFI overlap extensively in the ventricular zone of visual, auditory and somatosensory cortex. This differs from the mouse in which COUP-TFI and SP8 show little overlap. Combinatorial  expression of COUP-TFI and SP8 could maintain a common genetic identity for future primary sensory areas (visual, auditory and somatosensory) and a partially shared identity with SP8-expressing frontal motor cortex with which these sensory areas will interconnect, along with allied association cortex, via dorsal sensorimotor pathways. In mouse COUP-TFII is confined to a very small portion of the posterior cortex but in human is expressed extensively throughout the ventral temporal  and ventral posterior cortex where it overlaps with COUP-TFI expression. Perhaps the expansion of cortical COUP-TFII expressing territory in human fetal brain mirrors the increased size and complexity of the association areas of the ventro-temporal cortex.  An extension of this observation is that dorsal and ventral hippocampus are also differentiated by combinatorial expression of SP8/COUP-TFI and COUP-TFII/COUP-TFI respectively. Each domain has distinct functions and distinct efferent and afferent connections. It appears that the protomap for human hippocampal specialisation is laid down early in development.

It has been a 15 year journey to reach the beautiful images in Figure 4 with many interesting diversions along the way; for instance, when studying PAX6 expression we discovered a new class of progenitor cell in the subventricular zone of the cortex [11] which was subsequently shown to be a new class of radial glia [12]. We now know that humans as well as rodents have a protomap to guide cortical development, but this protomap is plastic and can be perturbed by genetic alteration, pharmacological interventions and lesions. Although more investigation is needed, it seems highly likely that the protomap has evolved in complexity as the cerebral cortex has evolved in complexity, rather than entirely new mechanisms being required to shape the cortex’s functional organisation, although, as ever, more research is needed to test this assertion. Ensuring that neurons in the cortex have the right regional and functional identity is crucial to establishing their long and short range connectivity, deficits in which are proposed to underlie neurodevelopmental orders such as autism and schizophrenia, so there is good reason to extend this journey a while longer yet.

References

1.  Basu A, Graziadio S, Smith M, Clowry GJ, Cioni G, Eyre JA (2010) Developmental plasticity connects visual cortex to motoneurons after stroke. Annals of Neurology 67:132-6.
2.  Rakic P (1988) Specification of cerebral cortical areas. Science 241:170.
3.  Bishop KM, Goudreau G, O’Leary DDM (2000) Regulation of area identity in the mammalian neocortex by Emx2 and Pax6. Science 288:344-9.
4.  Muzio L, Di Benedetto B, Stoykova A, Boncinelli E, Gruss P, Mallamaci A (2002) Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical primordium. Cerebral Cortex 12:129-39.
5.  Clowry GJ, Alzu’bi A, Harkin LF, Sarma S, Kerwin J, Lindsay S (2017) Charting the protomap of the human telencephalon. Seminars in Cell and Developmental Biology, Epub ahead of print, doi.org/10.1016/j.semcdb.2017.08.33.
6.  Bayatti N, Sarma S, Shaw C, Eyre JA, Vouyiouklis DA, et al (2008) Progressive loss of PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates with translocation of EMX2 to the cortical plate during human cortical development. European Journal of Neuroscience 28: 1449-1456.
7.  Ip BK, Wappler I, Peters H, Lindsay S, Clowry GJ, Bayatti N (2010) Investigating gradients of gene expression involved in early human cortical development. Journal of Anatomy 217: 300-311.
8. Ip BK, Bayatti N, Howard NJ, Lindsay S, Clowry GJ (2011) The corticofugal neuron-associated genes ROBO1, SRGAP1, and CTIP2 exhibit an anterior to posterior gradient of expression in early fetal human neocortex development. Cerebral Cortex 21: 1395-1407.
9.  Buckner RL, Krienen FM (2013) The evolution of distributed association networks in the human brain. Trends in Cognitive Sciences 17: 648-65.
10.  Alzu’bi A, Lindsay SJ, Harkin LF, McIntyre J, Lisgo SN, Clowry GJ (2017) The transcription factors COUP-TFI and COUP-TFII have distinct roles in arealisation and GABAergic interneuron specification in the early human fetal telencephalon. Cerebral Cortex 27: 4677-4690.
11.  Bayatti N, Moss JA, Sun L, Ambrose P, Ward JFH, Lindsay S, Clowry GJ (2008) A molecular neuroanatomical study of the developing human neocortex from 8 to 17 postconceptional weeks revealing the early differentiation of the subplate and subventricular zone. Cerebral Cortex 18: 1536-1548.
12. Lui, J.H. Hansen, D.V., Kriegstein, A.R. 2011. Development and evolution of the human neocortex. Cell 146: 18–36.

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