My research interest is the evolution of multicellularity. How did cells ‘learn’ to communicate with each other to build a structure that is more complex than its parts and shows new emergent behaviour? Which and how many new genes would be required to transform a unicellular ancestor into a well-organised multicellular structure? The Nature Communications Article from our lab that was published recently (1) sets out to answer some of those questions.

Most of us will be familiar with the type of multicellularity, which evolved in animals, some fungi and plants: cells derived from a zygote continue to divide, but remain attached to each other and eventually differentiate into the different cell types that form the tissues of the organism. All cells are genetically identical and altruistic differentiation into somatic cells that support the propagation of the germline has no cost to them. A quite different case is the colonial multicellularity of social amoebas, which we are studying in our lab. Here, individual cells that can be genetically distinct come together and create a multicellular fruiting structure, consisting of spores and stalk cells.  The stalk cells have to altruistically die to support spores. When the amoebae are not genetically identical, conflicts of interest can arise, such as cheating by avoiding stalk cell differentiation. Just like multicellularity by adhesion, colonial multicellularity evolved multiple times (2,3), suggesting that colonial organisms have devised mechanisms to deal with genetic conflict.

The Dictyostelid social amoebas can be subdivided into four major groups, which differ in the size and shape of fruiting bodies, the presence of an intermediate migratory form, the “slug” and the number of cell types, which is largest in group 4. In addition, group 4 species pre-differentiate amoebas into the correct ratio of prespore, prestalk and the other supporting cell types, whereas in groups 1-3 all amoebas first differentiate into prespore cells that then only locally dedifferentiate into stalk cells (Figure 1).

In Dictyostelia, cell proliferation is entirely separated from multicellular development and we can therefore loosely define “multicellularity genes” as genes that are essential for multicellular development, but not for cell proliferation. We wanted to know to what extent such genes were already present in the unicellular ancestors of Dictyostelia and how such genes changed or appeared in the course of Dictyostelid evolution to increase the morphological and behavioural complexity of the organisms.  To achieve this we sequenced three genomes that represented groups 1, 2 and 3 of Dictyostelia. The genome of two group 4 species, D. discoideum and D.purpureum were already available as well as the genomes of three unicellular Amoebozoa. Additionally we investigated how expression of all genes in these genomes is regulated during their development by high throughput RNA sequencing. This allowed us to trace gene evolution across the whole phylogenetic tree of social amoebas and their unicellular Amoebozoan relatives. From previous studies, 385 genes in D.discoideum were known to produce a defect in multicellular development when disrupted. We found that 305 of these genes were already present in unicellular Amoebozoa. The majority is conserved in all Dictyostelia regarding the conservation of domains and expression regulation. However, 80% of those genes, which are mainly cytosolic and nuclear proteins and protein kinases, are already present in their unicellular relatives.  Eighty genes were unique to Dictyostelia and this set was enriched in plasma membrane and secreted or extracellularly exposed proteins, G-protein coupled receptors and sensor histidine kinases. Also, a set of 37 proteins that were only conserved in group 4 or groups 3 and 4 were highly enriched in plasma membrane and secreted or exposed proteins (Figure 2).

For conserved genes, we also investigated whether their developmental regulation and their protein functional domains were conserved. If not, we scored how such changes were distributed across the Dictyostelium phylogeny. Logically, one expects such changes to be greater when the species are evolutionary more distant from each other. In case of functional domains, the changes were mostly scattered across the phylogeny (Figure 3), suggesting that changes in protein function did not contribute greatly to changes in phenotypic complexity. However, changes in developmental regulation occurred much more frequently between group 4 on one hand and groups 1-3 on the other, than between branches I and II that are evolutionary more distant. Because group 4 species are also phenotypically most distinctive (Figure 1), this indicates that phenotypic innovation in group 4 was more likely to be caused by changes in gene expression than changes in protein function. Finally, investigating the closest relatives of the 385 genes in species outside the Amoebozoa, we found that a relatively large percentage had closest homologs in bacteria. Further scrutiny identified four genes that were only present in Dictyostelia and bacteria and likely entered Dictyostelia by lateral gene transfer. Three of these genes synthesise three out of the five non-peptide signals that induce cell differentiation in D.discoideum: c-di-GMP, DIF-1 and discadenine (4-7).

In conclusion, it seems that innovation to multicellularity largely relied on repurposing of existing genes that were already present in the unicellular ancestor. Conversely, genes encoding exposed and secreted proteins with likely roles in adhesion and cell communication and the sensors to detect these signals appeared only in the multicellular forms, with genes for some novel signal molecules being acquired directly from bacteria. Furthermore, changes in gene regulation appear to have been more important for evolution of phenotypic complexity than changes in gene function.

References:

1. Glockner, G., et al., The multicellularity genes of dictyostelid social amoebas. Nature communications, 2016. 7: p. 12085.
2. Du, Q., et al., The Evolution of Aggregative Multicellularity and Cell-Cell Communication in the Dictyostelia. Journal of molecular biology, 2015. 427(23): p. 3722-33.
3. Schilde, C. and P. Schaap, The Amoebozoa. Methods in molecular biology, 2013. 983: p. 1-15.
4. Abe, H., et al., Structure of discadenine, a spore germination inhibitor from the cellular slime mold. Tetrahedron Letters, 1976. 17(42): p. 3807-3810.
5. Chen, Z.H. and P. Schaap, The prokaryote messenger c-di-GMP triggers stalk cell differentiation in Dictyostelium. Nature, 2012. 488(7413): p. 680-3.
6. Neumann, C.S., C.T. Walsh, and R.R. Kay, A flavin-dependent halogenase catalyzes the chlorination step in the biosynthesis of Dictyostelium differentiation-inducing factor 1. Proceedings of the National Academy of Sciences of the United States of America, 2010. 107(13): p. 5798-803.
7. Saito, T., A. Kato, and R.R. Kay, DIF-1 induces the basal disc of the Dictyostelium fruiting body. Developmental biology, 2008. 317(2): p. 444-53.

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The Laboratory of Regulatory Evolution (Tschopp group) at the Zoological Institute, University of Basel, Switzerland, is hiring for a lab manager position.

We are interested in how phenotypic diversity is generated during vertebrate embryogenesis. As a model system, we are studying the development of the vertebrate skeleton with its associated neuromuscular system. We address these questions using a range of methods, including experimental embryology; functional genomics; cell culture and viral gene delivery; genome editing (CRISPR-Cas9); bioinformatics and in silico modeling.
For more information please visit http://evolution.unibas.ch/tschopp/research/index.htm

The tasks associated with this position will include managing and streamlining standard lab procedures, ordering, as well as experimental work (cell culture, histology, immunohistochemistry).

Your profile
Successful candidates will have a background in molecular biology and/or lab managing. You enjoy working in a team environment, and are proficient in German and have a basic knowledge of English. You are interested in learning and developing new technology to address long-standing questions in developmental and evolutionary biology.

We offer you
– Highly interactive and interdisciplinary research environment
– Attractive employment conditions, very competitive salary by international standards
– The position might get expanded to 100% employment, external funding permitting

Application / Contact
Please send your application with a brief statement of motivation, a current CV and contact(s) for references (where applicable) to patrick.tschopp@unibas.ch
Evaluation will begin on Sept. 1st 2016 and suitable candidates will be contacted shortly after.

The University of Basel is an equal opportunity employer and encourages applications from female candidates.

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The Fribourg Graduate School of Life Sciences (FGLS) is an interdisciplinary and international graduate school, which offers a coordinated doctoral programme in life sciences at the University of Fribourg. It addresses doctoral fellows in the fields of biology, biochemistry, molecular medicine, chemistry, physics, bioinformatics and mathematics who have a life science focus. State-of-the-art theoretical and experimental research will lead to a Doctor of Philosophy (PhD).

The Faculty of Sciences offers the following degrees related to biology:

• PhD in Biology
• PhD in Biochemistry
• PhD in Bioinformatics

Currently, we are recruiting students in the fields of:

• Protein Homeostasis in Autophagy
• Plant Cell Polarity
• Developmental and Behavioural Neurobiology
• Chronobiology
• Lipid Homoestasis in yeast
• Nutrient signalling and growth control
• Molecular and cellular Neurobiology
• Regulation of plant symbiosis
• Community Ecology

We offer an integrated research and training programme which leads to a PhD after three to four years. The entire programme is run in English and includes a supervision and mentoring programme, as well as courses of novel technologies and soft skills. We expect applicants to have an excellent university degree and to be motivated and interested in interdisciplinary research subjects.
Excellent communication skills in English are of benefit.

Application procedure:

If you are interested send an application including

• a CV and names of three referees
• a copy of your master degree (or the current academic transcript)
• a statement of your research interests in the selected field(s)

to Ms Adeline Favre. Only complete application files will be considered.

Application is open until September 18th, 2016.

Interviews will take place in October 2016. Selected students will start latest January 2017.

More information

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Here are the highlights from the current issue of Development:

Defining Polycomb complexes with AEBP2

Polycomb repressive complex 2 (PRC2) directs methylation of histone H3 K27 (H3K27me), a repressive histone mark. Mutations in PRC2 complex components cause a spectrum of developmental defects, including posterior transformation of the skeleton due to misexpression of Hox cluster genes. In addition to the core complex components, a number of substoichiometric accessory proteins have been identified, but the functions of these remain incompletely understood. One of these factors is AEBP2, a zinc-finger domain-containing protein that has been proposed to play a role in PRC2 recruitment. On p. 2716, Sarah Cooper, Neil Brockdorff and colleagues evaluate the role of AEBP2, generating a knockout mouse and mutant embryonic stem cells (ESCs). Surprisingly, the phenotype observed upon Aebp2 depletion is not loss of PRC2 function, but rather a Trithorax phenotype (anteriorisation of the skeleton) associated with increased Polycomb activity. In the absence of Aebp2, an atypical PRC2 complex appears to form, which may be responsible for the mild enhancement in H3K27me levels. The authors therefore propose that AEBP2 functions primarily to define the composition of PRC2 complexes, and hence modulate their activity.

A role for DISC1 in astrogenesis

Mutations in human DISC1, a protein associated with the dynein motor complex, have been implicated in schizophrenia. In mouse, knockdown of DISC1 causes a number of phenotypes, including premature neuronal differentiation and impaired neurite and axonal outgrowth, while Disc1 mutants, although viable and fertile, show strong behavioural defects. However, the potential functions of DISC1 in glia, including astrocytes, have been less studied, even though disruption of astrocytes has been reported in schizophrenic patients. Jianwei Jiao and co-workers (p. 2732) therefore set out to assess the consequences of Disc1 loss- or gain-of-function in mouse astrocytes. Both in vivo and in vitro, they find that Disc1 depletion impairs astrogenesis, while overexpression promotes differentiation down the astrocyte lineage. Mechanistically, the authors show that DISC1 modulates RAS/MEK/ERK signalling, which is known to be important for astrogenesis: upon Disc1 deletion, MEK and ERK phosphorylation (and hence activation) is impaired. In this context, interaction between DISC1 and the RAS-association domain protein RASSF7 appears to be important: as with DISC1, overexpression of RASSF7 promotes astrocyte differentiation. Although the potential contribution of this astrogenic activity of DISC1 to the schizophrenia phenotype has yet to be analysed, these data suggest that modulation of astrocyte differentiation may be relevant for this neuropsychiatric disorder.

Set(db1)ting up the genome for meiosis and mitosis

During oocyte maturation, meiotic arrest and fertilisation, multiple processes – deposition of maternal transcripts and proteins, various signalling events, DNA replication, chromosome segregation and so on – must be tightly orchestrated to ensure that the resultant zygote is viable. Many of these processes require chromatin-driven modulation of transcription. Antoine Peters and colleagues (p. 2767) have uncovered an important role for the H3K9 methyltransferase Setdb1 in oocyte meiosis and early zygotic development. Mouse embryos depleted for maternal Setdb1 fail to progress to the blastocyst stage. In mutant oocytes, meiotic progression is impaired and multiple defects in spindle organisation and chromosome segregation can be observed. To try and understand the reason for these defects, the authors performed RNAseq analysis, finding misregulation of multiple genes with roles in cell division. Moreover, Setdb1-deficient oocytes show increased expression of multiple retrotransposons, consistent with the known role of Setdb1 in restraining retrotransposon expression in embryonic stem cells (although the families of elements regulated differ in the two contexts). Finally, the authors show that maternal Setdb1-deficient embryos suffer from similar defects in mitosis to those observed in oocyte meiosis. Thus, these data establish Setdb1 as a crucial regulator of meiotic and mitotic progression in the oocyte and early embryo.

On the IMPortance of localised axonal mRNAs

In the nervous system, certain mRNAs are transported along axons and show localised translation. This is thought to be important for axon-autonomous regulation of, for example, growth cone turning and guidance. However, we still have an incomplete understanding of which mRNAs are localised, how their transport and translation are controlled, and how this impacts neuronal development and function. The IMP1 RNA-binding protein is known to play a role, particularly in controlling local expression of β-actin in neurons and other cell types, and John Flanagan and colleagues (p. 2753) now investigate the function of its relative IMP2. In the developing mouse nervous system, IMP2 shows specific localisation to axon tracts. Identification and analysis of the mRNAs to which IMP2 binds reveals a large number of putative targets, including many associated with axon guidance, cell migration and cytoskeletal organisation. Consistent with this, IMP2 knockdown in the developing chick spinal cord leads to growth cone stalling and failed axon midline crossing at the floor plate. This phenotype is reminiscent of loss of one of the identified IMP2 targets, namely the Robo1 receptor, whose axonal protein levels are reduced upon IMP2 knockdown. Together, these data identify a new player in axonal mRNA regulation and provide a valuable dataset for further analysis of the role of IMP2 and its targets.

Plus…

Size regulation blossoms in Kobe

Coincident with the blossoming of the sakura was the 14th annual CDB Symposium hosted by the RIKEN Center for Developmental Biology in Kobe, Japan. This year’s meeting, ‘Size in Development: Growth, Shape and Allometry’ focused on the molecular and cellular mechanisms underlying differences in size and shape and how they have evolved. Here, Iswar Hariharan highlights the advances presented at this meeting and the open questions in the field. See the Meeting Review on p. 2691

Direct lineage reprogramming via pioneer factors; a detour through developmental gene regulatory networks

Growing evidence suggests that current methods of direct lineage conversion may rely on the transition through a developmental intermediate. Here, Sam Morris explores pioneer transcription factor-driven direct lineage reprogramming between mature cell states, proposing that this depends on reversion to a developmentally immature state. See the Hypothesis article on p. 2696

Blood vessel formation and function in bone

Blood vessels in the skeletal system control multiple aspects of bone formation and provide niches for hematopoietic stem cells that reside within the bone marrow. Here, Kishor Sivaraj and Ralf Adams provide an overview of the architecture of the bone vasculature and discuss how blood vessels form within bone, how their formation is modulated, and how they function during development and fracture repair. See the Review on p. 2706

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The Laboratory of Regulatory Evolution (Tschopp group) at the Zoological Institute, University of Basel, is hiring for two fully funded PhD positions.

Our research interests focus on two main questions: 1. How is phenotypic diversity generated during vertebrate embryogenesis? And 2. how can developmental processes be modified to drive morphological evolution? We are particularly interested in investigating how the evolution of gene regulation is underlying these phenomena. As a model system, we are studying the development of the vertebrate skeleton with its associated neuromuscular system.

In a first project, we will investigate the gene regulatory networks underlying the generation of skeletal cell types, originating from distinct embryonic sources and in different species. This will allow us to assess the developmental and evolutionary constraints on gene regulation during cell type specification. Secondly, we are interested how cell specification and embryonic patterning are intertwined. To this end, we will study the specification of synovial joints during the embryonic outgrowth of digits, a process contributing important aspects of the patterning diversity seen in the hands and feet of vertebrates.
Both projects build on solid foundations of confirmed preliminary data. For more information please visit http://evolution.unibas.ch/tschopp/research/index.htm

We will address these questions using a range of experimental methods, including embryology in chicken, mice and fish; functional genomics (RNA-seq, ChIP-seq, ATAC-seq, STARR-seq); cell culture and viral gene delivery; genome editing (CRISPR-Cas9); bioinformatics and in silico modeling.

Successful candidates will have a background in molecular and/or developmental biology, and ideally will have a basic understanding of Unix and the R language for statistical computing.

Please send your application with a brief statement of motivation, a current CV and contact(s) for references (where applicable) to patrick.tschopp@unibas.ch
Evaluation will begin on Sept. 1st 2016 and suitable candidates will be contacted shortly after.

The University of Basel is an equal opportunity employer and encourages applications from female candidates.

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“My dear, here we must run as fast as we can, just to stay in place.

And if you wish to go anywhere you must run twice as fast as that.”
L. Carroll ‘Alice Through the Looking Glass’

We write this while we finish the last experiments for the final Show n’ Tell on Saturday full of reluctance to finish this course. Samples fly all over the lab; solutions are changed and something blue boils somewhere in the room.

Looking back, six weeks ago we had an approximate idea of what the MBL Embryology Course was about: people doing science 24/7, lectures and a lot of organisms with names you can barely pronounce. What we did not know is that the experience was all of that and more.

The first day was weird. People hanging their posters on the walls, rushing to get ready to tell other people about what is basically their life in the lab. After a while, everybody was talking with each other about science and how much they want to try new things. Our excitement grew as we realized that we would not only get to experience a plethora of organisms, but we would also learn from peers who are expert at widely diverged backgrounds. Little did we know about what we were really in for, though!

After that, the routine was as follows:

You wake up, rush to stuff yourself with breakfast, get a coffee and run to the Speck Auditorium to hear about the nuts and bolts of a new organism. From sea urchins to worms (flat or not), through articulated arthropods, squishy jellyfish and ctenophores, hemichordates, urochordates, glowing zebrafish or little mice, we learned about how they develop. One of the first things you realize is the kind of amazing things people are doing on this crazy endeavor of understanding how life works. All organisms share common features and are different from each other, highlighting how important all of them are. The second thing you realize is how passionate people are about their work, and you cannot help but remember why you became a scientist on the first place.

After the lectures we had what’s been called The Sweat Box for many years. This consists on a freestyle Q&A session about the contents of the lecture that usually would diverge on questions about anything related to the subject. During this time, we had the opportunity to discover how much people know about their (and other) organisms, and how they have contributed to their field and biology in general. As the course went on, our confidence grew to ask seemingly the strangest and deepest of questions. These turned out to be questions of broad interest or potential projects, which may highlight the key points of developmental research for the next decade.

After lunch, we had laboratory until the (usually very, very late) evening. The laboratories consisted on a brief introduction to the organism and the available tools. Then, it was up to you which type of question you wanted to ask: Big or small, simple or complex, you were given complete freedom and the TAs and PIs would usually challenge us to try new and classic experiments. You didn’t need to have any hypothesis or rigorous experimental design, as there should be no limitation for your curiosity. You just followed your intuition to give it a try for anything jumping up from your mind. It was a great chance to examine your crazy ideas, which your advisor might not allow you to test at your home laboratory, applying new available technologies to try experiments that were not previously feasible. Looking back, this curiosity-driven science is what we think that makes being a scientist an awesome job and we encourage everybody to do it, because that’s where magic happens. What would happen if you fuse two sea urchin embryos? Would a worm develop normally if you spin it down in the centrifuge? What is the smallest piece of an animal that would regenerate? Is that experiment mentioned earlier during the lecture really impossible? These questions are also important, and we had so much fun trying to answer them. Most of our experiments did not work, but science is about that, too: What basic principle have you learned by doing that experiment?

(It is important to mention that it is great seeing how the kind of experiments we the students propose still can surprise somebody that has been working in the field for many years. This is one of the great things about science: the capacity of being amazed)

Most importantly for our research in the ‘real world’, we had the opportunity to try new techniques and explore the use of tools we had never otherwise been able to use. For each established organism*, there are usually are some common experimental skills which are not utilized by researchers studying other organisms. We had the chance to learn many interdisciplinary, useful experimental skills and tool-making methods that can be applied to different organisms to broaden the possibility and feasibility of experimental designs in each module. Moreover, the training on different types of microscopes and imaging techniques enabled us to utilize appropriate methods, generating high-resolution images for different purposes and organisms. We could even separate overlapping spectra to distinguish (up to eight!!) different fluorescent markers on one sample for co-localization studies.

Every two weeks we got to present our data in the so-called Show n’ Tell. The recipe for it is a powerpoint presentation, a timer and people waiting to be amazed by the kind of data you collected in two weeks. During the time you were given, it was up to you presenting (or even dancing!) one, two or n experiments. It was very common seeing jaws dropping or people clapping, and everybody was smiling as they saw what a great time people had trying new experiments or collecting beautiful images. Our evening was spent laughing and embracing each other’s scientific creativity, an essential factor for the development of us as scientists.

Starting from first cell division, we had the opportunity to visualize the various types and patterns of cleavage processes among different organisms. We got to witness the beauty of biodiversity and how precisely it is regulated. When observing how a new life begins and grows, it is difficult to describe how deeply we were touched by the exquisiteness of life.

But not everything was about science! We had Sundays off, that we usually spent (not necessarily in this order) doing laundry, sleeping or exploring the beautiful towns of Woods Hole and Falmouth. We also had the opportunity of going Whale Watching, participating in the Independence Day costume parade and swimming in the bioluminescent ocean. During these six weeks of being awake at all hours, failing and succeeding together and enjoying our time off together, we became closer and closer to each other. With our virtues and defects, we have become friends.

Because science should be about that: whether your organism is big or small, squishy or hard, pigmented or transparent, we all are in the same boat. We all are trying to understand how life works, and we all should collaborate towards a better understanding of (in this case) embryology and development.

We’d like to finish this little story thanking our Course Directors, Richard and Alejandro, who made all of this possible. We’d also like to thank all the Faculty and TAs that spent endless hours preparing all the experiments so we could have fun in the lab. We couldn’t have done any of this without our amazing Course Assistants Wes, Chris and Brittany, who took care of everything and are a fundamental part of the course. We also appreciate the endless support from outside of course: the specialists from Zeiss and Leica, teaching us how to generate amazing images, and other sponsor companies providing the latest-model equipment for us to perform fancy experiments. And last, but not least, we’d like to thank you reader, for being curious enough to read this little piece. Never stop being amazed and get out your comfort zone, and magic will happen.

Joaquín, Aleisha and Tsai-Ming
MBL Embryology Course, Class of 2016

Joaquín Navajas Acedo is a Grad Student from the Grad School of the Stowers Institute for Medical Research in Kansas City, Missouri (USA). He is currently working on the establishment of cell polarity using zebrafish at the Piotrowski Lab (http://research.stowers.org/piotrowskilab)

Aleisha Symon is a PhD student from Monash University in Melbourne (Australia). She is currently researching genes that are involved in the development of the mammalian testis at the Hudson Institute of Medical Research in the Harley lab (http://hudson.org.au/profile-prof-vincent-harley/)

Tsai-Ming Lu is a PhD student from Marine Genomics Unit at Okinawa Institute of Science and Technology (OIST) Graduate University, Okinawa, Japan. He is working on the genome project of dicyemid mesozoan, Dicyema japonicum, a parasite inhabiting in the renal sac of octopus, to understand the mechanisms of regressive evolution and adaptive radiation (https://groups.oist.jp/mgu)

PS: Some of us live-tweeted during the 6 weeks we spent at the MBL using the hashtag #embryo2016. If you want to get a good idea about what the course was like, please visit: https://twitter.com/search?q=%23embryo2016&src=typd

*The usage of the expression ‘model organism’ and ‘non-model organism’ was passionately discussed during one of the sessions in the Sweat Box. Since each organism can be a model, we decided that the term ‘canonical’ or ‘established’ would be more appropriate or not even adding a label. There is a recent article that discusses the matter (http://www.cell.com/current-biology/fulltext/S0960-9822(16)30604-2)

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Our latest monthly trawl for preprints. See June’s post for background, and let us know if we missed anything

This month we found preprints on various themes in developmental biology, as well as a lot of work that we hope will be of general interest to the community.

One of July’s most talked-about preprints tackled a subject felt keenly by most scientists, let alone developmental biologists: the journal impact factor. Vincent Lariviere, Stephen Curry and colleagues from Springer, AAAS, PloS, The Royal Society, eLife and EMBO presented an alternative method to generate citation distributions. July’s tranche also features zebrafish lamination and echinoderm regeneration, a hefty dose of evo-devo,  plenty of techniques and resources, and expanded genomes for humans, flies and mice.

The preprints listed below are hosted on biorxiv, arxiv and F1000Research.

Happy preprinting!

Developmental Biology & Related

• Precision of readout at the hunchback gene. Jonathan Desponds, Huy Tran, Teresa Ferraro, Tanguy Lucas, Carmina Perez Romero, Aurelien Guillou, Cecile Fradin, Mathieu Coppey, Nathalie Dostatni, Aleksandra M Walczak
•  Nkx2.1 regulates the proliferation and cell fate of telencephalic astrocytes during embryonic development. Shilpi Minocha, Delphine Valloton, Yvan Arsenijevic,  Jean-Rene Cardinaux, Raffaella Dreier Guidi,  Jean-Pierre Hornung, Cecile Lebrand
• Independent modes of ganglion cell translocation ensure correct lamination of the zebrafish retina. Jaroslav Icha, Christiane Grunert, Mauricio Rocha-Martins, Caren Norden
• Foxc1 Controls Cell Fate Decisions During Transforming Growth Factor β Induced Epithelial to Mesenchymal Transition Through the Regulation of Fibroblast Growth Factor Receptor 1 Expression. Alexander Hopkins, Mackenzie L Coatham, Fred B Berry
• R-spondin1 regulates muscle progenitor cell fusion through control of antagonist Wnt signaling pathways. Floriane Lacour, Elsa Vezin, Florian Bentzinger, Marie-Claude Sincennes, Michael A Rudnicki, Robert D Mitchell, Ketan Patel, Marie-Christine Chaboissier, Anne-Amandine Chassot,  Fabien Le Grand
• Inhibition of cell proliferation does not slow down echinoderm neural regeneration. Vladimir Mashanov, Olga Zueva, Jose Garcia-Arraras
• Single Cell Pluripotency Regulatory Networks. Patrick S Stumpf, Rob Ewing, Ben D MacArthur
• A conceptual view at microtubule plus end dynamics in neuronal axons. André Voelzmann, Ines Hahn, Simon Pearce, Natalia P Sánchez-Soriano, Andreas Prokop
• The mitotic spindle in the one-cell C. elegans embryo is positioned with high precision and stability. Jacques Pecreaux, Stephanie Redemann, Zahraa Alayan, Benjamin Mercat, Sylvain Pastezeur, Carlos Garzon Coral, Anthony A Hyman, Jonathon Howard 
• A Dynamic Mode of Mitotic Bookmarking by Transcription Factors. Sheila S Teves, Luye An, Anders S Hansen, Liangqi Xie, Xavier Darzacq, Robert Tjian
• The genome of the crustacean Parhyale hawaiensis: a model for animal development, regeneration, immunity and lignocellulose digestion. Damian Kao, Alvina G Lai, Evangelia Stamataki, Silvana Rosic, Nikolaos Konstantinides, Erin Jarvis, Alessia Di Donfrancesco, Natalia Pouchkina-Stantcheva, Marie Semon, Marco Grillo, Heather Bruce, Suyash Kumar, Igor Siwanowicz, Andy Le, Andrew Lemire, Cassandra Extavour, William Browne, Carsten Wolff, Michalis Averof, Nipam H Patel, Peter Sarkies, Anastasios Pavlopoulos, Aziz Aboobaker
• Transition from environmental to partial genetic sex determination in Daphnia through the evolution of a female-determining incipient W-chromosome. Celine M. O. Reisser, Dominique Fasel, Evelin Hurlimann, Marinela Dukic, Cathy Haag-Liautard, Virginie Thuillier, Yan Galimov, Christoph R Haag
• Deep, Staged Transcriptomic Resources for the Novel Coleopteran Models Atrachya menetriesi and Callosobruchus maculatus. Matthew Alan Benton, Nathan James Kenny, Kai Hans Conrads, Siegfried Roth, Jeremy A Lynch
• The evolutionary origin of bilaterian smooth and striated myocytes. Thibaut Brunet, Antje H. L. Fischer, Patrick R. H. Steinmetz, Antonella Lauri, Paola Bertucci, Detlev Arendt

Techniques

• Massively multiplex single-cell Hi-C. Vijay Ramani, Xinxian Deng, Kevin L Gunderson, Frank J Steemers,Christine M Disteche, William S Noble, Zhijun Duan, Jay Shendure
• Construction of thousands of single cell genome sequencing libraries using combinatorial indexing. Sarah A Vitak, Kristof A Torkenczy, Jimi L Rosenkrantz, Andrew J Fields, Lena Christiansen, Melissa H Wong, Lucia Carbone, Frank J Steemers, Andrew Adey
• Massively parallel digital transcriptional profiling of single cells. Grace X.Y. Zheng, Jessica M Terry, Phillip Belgrader, Paul Ryvkin, Zachary W. Bent, Ryan Wilson, Solongo B. Ziraldo, Tobias D. Wheeler, Geoff P. McDermott, Junjie Zhu, Mark T. Gregory, Joe Shuga, Luz Montesclaros, Donald A Masquelier, Stefanie Y. Nishimura, Michael Schnall-Levin, Paul W Wyatt, Christopher M. Hindson, Rajiv Bharadwaj, Alexander Wong, Kevin D. Ness, Lan W. Beppu, Joachim Deeg, Christopher McFarland, Keith R. Loeb, William J. Valente, Nolan G. Ericson, Emily A. Stevens, Jerald P. Radich, Tarjei S. Mikkelsen, Benjamin J. Hindson, Jason H Bielas
• Rapidly evolving homing CRISPR barcodes. Reza Kalhor, Prashant Mali, George M Church
• Genome Editing With Targeted Deaminases. Luhan Yang, Adrian Briggs, Wei Leong Chew, Prashant Mali, Marc Guell, John Aach, Daniel Goodman, David Cox, Yinan Kan, Emal Lesha, Venkataramanan Soundararajan, Feng Zhang, George Church
• Bright photoactivatable fluorophores for single-molecule imaging. Luke D Lavis, Jonathan B Grimm, Brian P English, Heejun Choi, Anand K Muthusamy, Brian P Mehl, Peng Dong, Timothy A Brown, Jennifer Lippincott-Schwartz, Zhe Liu, Timothée Lionnet
• In vivo mapping of tissue- and subcellular-specific proteomes in Caenorhabditis elegans. Aaron W Reinke, Raymond Mak, Emily R Troemel, Eric J Bennett
• iDamIDseq and iDEAR: An improved method and a computational pipeline to profile chromatin-binding proteins of developing organisms. Jose Arturo Gutierrez-Triana, Juan Mateo, David Ibberson, Joachim Wittbrodt
• RNA-seq mixology: designing realistic control experiments to compare protocols and analysis methods. Aliaksei Z Holik, Charity W Law, Ruijie Liu, Zeya Wang, Wenyi Wang, Jaeil Ahn, Marie-Liesse Asselin-Labat, Gordon K Smyth, Matthew E Ritchie
• Whose sample is it anyway? Widespread misannotation of samples in transcriptomics studies. Lilah Toker, Min Feng, Paul Pavlidis
• Ingested double-stranded RNA and their mobile RNA derivatives have different requirements for gene silencing in C. elegans. Pravrutha Raman, Soriayah Zaghab, Edward Traver, Antony Jose

In Silico Modelling/Tools/Stats

• Hydrodynamic theory of tissue shear flow. Marko Popović, Amitabha Nandi, Matthias Merkel, Raphaël Etournay, Suzanne Eaton, Frank Jülicher, Guillaume Salbreux
• Triangles bridge the scales: how cellular processes cause tissue deformation. Matthias Merkel, Raphaël Etournay, Marko Popović, Guillaume Salbreux, Suzanne Eaton, Frank Jülicher
• Chaotic propagation of spatial cytoskeletal instability modulates integrity of podocyte foot processes. Cibele V Falkenberg, Evren U Azeloglu, Mark Stothers, Thomas J Deerinck, Yibang Chen, John C He, Mark H. Ellisman, James C. Hone, Ravi Iyengar, Leslie M. Loew
•  Information Isometry Technique Reveals Organizational Features in Developmental Cell Lineages. Bradly John Alicea, Thomas E. Portegys, Richard Gordon
• Stem Cell Networks. Eric Werner
• Contextual Hub Analysis Tool (CHAT): A Cytoscape app for identifying contextually relevant hubs in biological networks. Tanja Muetze, Ivan H. Goenawan, Heather L. Wiencko, Manuel Bernal-Llinares, Kenneth Bryan, David J. Lynn
• AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations. Mike Kucera, Ruth Isserlin, Arkady Arkhangorodsky, Gary D. Bader
• A statistical definition for reproducibility and replicability. Prasad Patil, Roger D. Peng, Jeffrey Leek

Genomics

• Deep Sequencing of 10,000 Human Genomes. Amalio Telenti, Levi T Pierce, William H Biggs, Julia di Iulio, Emily H.M. Wong, Martin M Fabani, Ewen F Kirkness, Ahmed Moustafa, Naisha Shah, Chao Xie, Suzanne C Brewerton, Nadeem Bulsara, Chad Garner, Gary Metzker, Efren Sandoval, Brad A Perkins, Franz J Och, Yaron Turpaz, J. Craig Venter
• Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation, and homozygous truncating mutations. Thomas Keane, Anthony Doran, David Adams, Kent Hunter,Jonathan Flint, Kim Wong
• A Thousand Fly Genomes: An Expanded Drosophila Genome Nexus. Justin B Lack, Jeremy D Lange, Alison B Tang, Russell B Corbett-Detig, John E Pool
• Stable C. elegans chromatin domains separate broadly expressed and developmentally regulated genes. Kenneth J Evans, Ni Huang, Przemyslaw Stempor, Michael A Chesney, Thomas A Down,  Julie Ahringer
• Functional and non-functional classes of peptides produced by long non-coding RNAs. Jorge Ruiz-Orera, Pol Verdaguer-Grau, José Luis Villanueva-Cañas, Xavier Messeguer, M Mar Albà

Publishing

• A simple proposal for the publication of journal citation distributions. Vincent Lariviere,  Veronique Kiermer,  Catriona J MacCallum,  Marcia McNutt,  Mark Patterson,  Bernd Pulverer,  Sowmya Swaminathan,  Stuart Taylor, Stephen Curry

(4 votes)

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In case you missed it, here’s a round up of our July content, with lots of developmental biology research highlights (inc. microfluidics, zebrafinches and 3D retinas), as well as some art, some history, and some opinions. Happy reading!

Research

Christopher Demers wrote about microfluidic chambers and how they can be a useful tool for developmental biologists,  Carloine Dillard introduced her recent work using Drosophila neural stem cells as a model for understanding the developmental origins of tumours, and Aysu Uygur told us what chickens and zebrafinches tell us about how to pattern different-sized tissues.

Marcos Simoes-Costa described how a fusion of classical and modern techniques helped to define and control the neural crest, Amelia Lane told the story of  differentiating photoreceptors from patient iPSCs and the great promise the technique has for retinal degeneration, and The DMDD wrote about how Zika has put birth defects in the spotlight.

Jingi Wu wrote about what ATAC-seq revealed about the chromatin landscape of the early embryo, and Wouter Masselink told us about a new cell type that orchestrates the development of the fin and sheds light on the fin-to limb transition.

Lab life

In our latest ‘Day in the Life’ series, Yoshimasa Hamada gave us an insight into what life is like in a cricket lab, Ngang Heok recounted his time in Singapore thanks to a Development travelling fellowship, and Rachna Narayanan wrote a report from the joint BSCB-BSDB Spring meeting in Warwick.

History and Art

Máté Varga told the fascinating story of George Streisinger, Hungarian founding father of zebrafish research and social activist (really worth setting aside twenty minutes to read this!)

Mark Hintze (developmental biologist) and Diana Gradinaru (artist) introduced their wonderful animation about the questions of developmental biology. The piece really gives wonderful context to the video:

Brexit

Gary McDowell, Vicki Metzis and Wouter Masselink gave us three quite different takes on what Brexit means for them and for science. A month on, all we know is that the uncertainty surrounding the UK science’s future is not going to be short lived.

Publishing

We started a new feature: this month in preprints, which aimed to collate and promote the latest devbio & related work deposited in preprint servers in the last month. Look out for July’s selection later today.

Jobs

Over on our jobs page, we had postdocs come up in Florida and Cologne, and PhDs in Groningen and Charleroi Brussels.

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The BSDB had its joint Spring Meeting with the BSCB earlier this year in April (10^th -13^th). It was my first time at the Meeting, which had been enthusiastically sold to me as “a good one, a fun one – they have a pub quiz!” and although I had been ‘sent to Coventry’, I have to confess, I had a great time. It was a busy 3 days, brimming over with interesting talks and stellar plenary and medal lectures. The concurrent sessions were on topics of interest for both cell and developmental biologists and so I ended up flitting between the talks of the concurrent sessions each day. Unfortunately, due to the impossibility of being in two places at once, there were excellent talks that I did miss and I apologise to these speakers for my non-attendance. I also want to say a big thank you to the speakers who have very kindly given me permission to write about the unpublished work they presented.

The meeting started, for me, with a Career Workshop on the Sunday afternoon. It was organised as a series of roundtable discussions with lecturers, group leaders, and people in industry, science publishing and communication. I got to speak to Paul Conduit, a Henry Dale Fellow at the University of Cambridge, Anne Wiblin from Abcam who provided the perspective of science life in industry, and Catarina Vicente from the Node, with whom I discussed the power of Twitter (and cakes) for communicating science.

Sunday evening’s plenary lectures were given by stalwarts – Mark Kirschner gave the BSDB Plenary Lecture and Ruth Lehmann the BSCB Plenary Lecture.

Mark Kirschner’s lecture sought to give quantitative answers to a fundamental question – “what is the economy of RNA and protein in embryonic development?’ with impressive technology and precision. By examining the dynamics of RNA and proteins on a single cell level, the Kirschner group has been able to show that while the correlation between the mRNA and protein levels is 0, the protein synthesis rate correlates with the mRNA synthesis and decay rates (Peshkin et al. 2015).

Jordan Raff, while introducing Ruth Lehmann, mentioned that he remembered her work, where injecting nanos mRNA into the anterior of the embryo caused the formation of an embryo with “essentially 2 bums”. Co-incidentally Ruth Lehmann came back to the “2 bums” embryo in her talk in the context of mitochondrial segregation in primordial germ cells. A second research story she presented was of mitochondrial maturation during germline cyst formation – developmentally regulated folding of the inner mitochondrial membrane into cristae is dependent on ATP-synthase dimer formation (Teixeira et al. 2015).

In a break with tradition, the student and post-doc social did not have a pub quiz, but instead we were put into random pairs and teams to build spaghetti towers and play science Pictionary. It was an excellent way to meet fellow attendees and bond over our total lack of talent at either drawing or building design (or complete mastery of, in a few cases).

Monday was a day packed with scientific goodness – 4 sessions of talks, 2 medal lectures and 2 poster sessions! The sessions of the morning were Cell and Tissue Architecture and Evolution. In the Cell and Tissue Architecture session I listened to Val Wilson talk about neuromesodermal progenitors (NMPs) – bi-fated cells at the caudal end of the mouse embryo who contribute either to the spinal cord or paraxial mesoderm, depending on their position in the progenitor region. She talked about NMP behaviour during the formation of the mid-trunk (Wymeersch et al. 2016). Olivier Hamant went on to talk about the role mechanical forces play in providing growth cues – microtubule dynamics in response to stress give the characteristic shape of sepals in Arabidopsis (Hervieux et al. 2016). Yara Sanchez Corrales showed how tube morphogenesis in the embryonic Drosophila salivary gland occurs. Cell division does not occur during the process and tube formation is driven entirely by cell shape changes and rearrangements. Their live cell imaging approach allows for the cell shape dynamics to be analysed in 3D.

In the Evolution session, I took in the talks of Marie-Ann Felix, Andrew Gillis and Marty Cohn. Marie-Ann Felix presented work aimed at understanding the effect of random mutation at the phenotypic level. They assayed the sensitivity of the vulval precursor cells of C. elegans to fate changes after the accumulation of random mutation and find that the P3.p vulval cell fate is most affected and is sensitive to mutations in many loci. This means that mutational effects can produce altered responsiveness to signalling pathways and, in this view, the P3.p cell fate is evolving the fastest. Andrew Gillis showed that Sonic hedgehog is required for gill arch anteroposterior polarity and for the branchial ray development in the gills of sharks, skates and rays (Chondrichthyans). This finding parallels paired fin development, giving traction to the hypothesis that there is serial homology between paired fins (and tetrapod limbs) and Chondrichthyan gill arches. Marty Cohn talked of the origin of cartilage – while true cartilage is considered to be unique to vertebrates, invertebrates like cuttlefish show cartilage-like tissue that develops via a deeply conserved gene regulatory network (Tarazona et al. 2016).

The afternoon sessions were Hijacking Cell and Developmental Processes and Polarity. In the Hijacking session, Shuchen Zhang presented her work trying to understand the genetic interactions of Sox2 that underpin its dual functions as a regulator of pluripotency in human embryonic stem cells and as a key factor in neural differentiation. Steve Jackson presented work on how cell-based screens in his lab have identified novel drug targets for cancer therapies, focussing on a PARP inhibitor that is now used in chemotherapy to treat hereditary ovarian cancers. In the Polarity session, Takashi Hiiragi showed that the apical domain of cells is instructive for the initial symmetry breaking in early mouse embryonic development by some fantastic live imaging. Nate Goehring showed us how through the use of novel small molecules, his lab has manipulated the activity and localisation of kinase PKC to understand the PAR polarity network in the C. elegans embryo. Ray Keller talked of the “mechanome” and the game plans – convergent extension, epithelial to mesenchymal transition and convergent thickening (driven by changes in cell affinity) – that tissues use to generate the forces required to drive morphogenesis in amphibians (Pfister et al. 2016).

The evening was host to BSCB’s Hooke Medal and BSDB’s Waddington Medal lectures. Tom Surrey was the recipient of this year’s Hooke Medal. He presented 3 facets of his lab’s research into understanding microtubule dynamics. Through impressive time-lapse fluorescence microscopy movies, we were shown the dynamics of microtubule growth, catastrophe (Duellberg et al. 2016) and nucleation (Roostalu et al. 2015) in in vitro reconstitutions. Tom Surrey’s medal lecture (and all other medal lectures of the meeting) can be watched here:

All movies of the 2016 BSCB/BSDB Spring Meeting

The recipient of the Waddington Medal was completely shrouded in secrecy until just minutes before the lecture, Ottoline Leyser (the BSDB president) even engaging the audience in a little guessing game to introduce him. It was Enrico Coen! He started his talk with a series of sketches of bulls by Picasso and posed the question – what is harder, describing something with every detail or capturing its essence? In a very cinematic presentation with beautiful images and movies, videos of collaborations with potter and glass-blower friends set to a lush soundtrack and a live demo of growth conflicts with melting plastic, Enrico Coen gave us the essence of his obsession – the snapdragon flower. The talk strongly resonated with the conference. References were made to it in almost every subsequent session and he might just have convinced everyone to drop everything they are doing and start studying snapdragons and bladderworts. I have it on good authority that he believes a good talk is like the movie High Noon. I know what you’ll be doing at your next lab meeting…

On Tuesday morning I attended the Growth and Cell division session. I heard Anja Geitmann talk about the mechanisms the pollen tube uses to grow towards the ovaries in plants and it genuinely seems a bit of a wrecking ball. Using a microfluidic device her group has been able to measure the pressure the pollen tube can exert – it is about 150kPa. That’s the pressure in a car tyre! Shane Herbert presented data showing that asymmetric cell divisions and Notch-Delta mediated lateral inhibition establishes the hierarchy of motility in the endothelial tip cells that allows for the leader-follower mode of cell migration in angiogenesis and Silvia Santos brought the session to a close by shedding some light on the temporal control of the cell cycle. Mitosis time is typically short and constant and insulated from the timing of early cell cycle phases. This seems to be regulated by the positive feedback of Cdk phosphorylation. Breaking the feedback leads to longer, more variable mitosis that is coupled to the interphase time.

The Graduate Student Symposium was held on Tuesday afternoon. Despite being fraught with technical difficulties, it was one of the most enjoyable and engaging sessions of the meeting. Kudos to the speakers for their quick thinking and improvisation in face of the ‘your-presentation-won’t-play’ challenge! We heard about (and saw, when the computers co-operated) Mycobacterium infection, cell divisions in motile cells and stretched tissues, centrosome clustering in cancers, neuroretinal self-organising aggregates, neural tube lumen formation, neuromesodermal progenitors, segmentation in spiders and flies, zebrafish cilia formation and calcium signalling in angiogenesis.

Uri Alon provided a brief and unexpected (i.e. not in the schedule) interlude titled the ‘The Life Scientific’ before the Woman in Science Medal talk. With a flip chart, a guitar, witty and tuneful songs that required back up singing by the audience, Uri Alon highlighted the need to acknowledge and discuss the emotional and subjective nature of the scientific process. Feeling lost, stuck and being in “the cloud” is all part of doing innovative science. Please, please watch his TED talk on YouTube, whether you are lost in “the cloud” or not. It is Game of Thrones-level essential viewing.

The Woman in Science Medal was awarded to Lidia Vasilieva for her work in understanding mechanisms of gene expression. Lidia began by highlighting the progress made in science to help women achieve their goals and then focussed on her work in understanding the regulation of gene expression. Her lab has discovered that exosome mediated RNA degradation, in co-operation with the splicing machinery, can regulate levels of mRNA (Kilchert 2015).

Abigail Tucker was the recipient of the first Cheryll Tickle medal. The Cheryll Tickle medal is being awarded by the BSDB to a mid-career female scientist for outstanding contributions to her field. And Cheryll Tickle herself was present to award the medal to Abigail Tucker. She quipped that she was rather glad that the BSDB went with her full name for the medal as “the Tickle medal” might suggest an award for something else (but the medal does feature a feather (!)). Abigail Tucker’s talk was a simultaneous career and life retrospective. She presented a career timeline, talking briefly about her PhD and postdoc work before taking us through the current activities of her lab studying the development of opossums, pit vipers and cobras. I imagine that this is the kind of work Indiana Jones would do, if he were a scientist. She also highlighted personal events of great significance on her career timeline. It is both inspiring and heartening to know that it is possible to have a thriving scientific career alongside a family.

Wednesday morning was a bit of tough start thanks to the late-night/early-morning revelry and dance floor antics that followed the conference dinner. But, I did manage to make it for Wendy Bickmore’s opener for the information processing session at 9.30am (!) about enhancer-promoter interactions studied by chromatin conformation capture and single molecule FISH. She was followed by Stefano De Renzis who showed how he can reconstitute invagination in embryonic Drosophila tissues that normally wouldn’t by optogenetically modulating the local actomyosin contractility.

I then caught the last 2 talks of the ageing and regeneration session. Yves Barral showed us how the bud lineage in budding yeast stays immortal – a diffusion barrier made of phytoceramides separates the mother and daughter preventing exchanging of membrane proteins and allows age to accumulate in the mother cell. Allison Bardin talked about mechanisms causing instability of the genome in adult stem Drosophila intestinal stem cells and how this affects homeostasis. Using an X-linked Gal80 construct she showed that mitotic recombination promotes loss of heterozygosity. She also showed that genomic rearrangements in these cells could lead to the spontaneous development of neoplasias in male flies (Siudeja et al. 2015).

Elena Scarpa, recipient of the Beddington medal for the best PhD thesis, presented her work in Roberto Mayor’s lab before Uri Alon brought the conference to a close. Elena showed the role of cadherins and the interplay of intracellular and external forces in contact inhibition of locomotion in migrating neural crest cells (Scarpa et al. 2015). Uri Alon spoke about how quantitative thinking could be brought into discussions of morphology and showed work from his lab where phenotypes had been studied using Pareto optimality. The approach is based on the logic that no phenotype can be good at all tasks and there is a trade-off with respect to the tasks to ensure maximal fitness, leading to optimal phenotypes. These phenotypes fall into simple shapes such as lines and triangles (Pareto fronts), the vertices representing an archetype – phenotypes that are specialised at a single task (Hart et al. 2015).

To sum up my experience at Warwick – I had spent 3 days being inspired by great talks, fascinated by all the new science I had heard, making new friends, having interesting discussions about my project and science in general. I discovered I am as hopeless at art as I am at origami and have no future at all as an architect. I was also strangely buoyed by the knowledge that most of my experiments are destined to fail. I returned home and fell into the dreamless slumber of a happy and exhausted child and woke up refreshed and ready to get lost in “the cloud”.

(1 votes)

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The laboratory of Developmental Genetics is looking for a PhD student to study the molecular mechanisms of neurogenesis in the developing mouse nervous system. The student will have to apply for a FNRS FRIA fellowship (http://www.fnrs.be/index.php/news-fnrs/517-fria-fresh-2016). The deadline for the application is the 30th August 2016.

The unit is located in the Biopark Charleroi Brussels South (http://ibmm.biopark-it.be/bced/), about 25 miles south of Brussels, in the Institute of Molecular Biology and Medecine (IBMM), a leading multidiciplinarity Institute from the faculty of Science and Medecine of the ULB (http://www.ulb.ac.be/rech/inventaire/unites/ULB578.html). The unit is part of the ULB Neuroscience Institute (http://uni.ulb.ac.be/groups/developmental-genetics/). The group is studying the molecular mechanisms that control the transition from neural stem cell to neurons in the developing vertebrate nervous system. The focus is on the role of some transcription factors in the molecular mechanisms that control neural progenitor maintenance, differentiation, and the generation of neuronal diversity. Major ongoing researches focus on the role of Dmrt transcription factors in cerebral cortex development and of Prdm transcription factors in pain perception, in health and diseases.
The laboratory uses in vivo genetic approaches in the mouse as well as gain- and loss-of-function experiments in the frog to approach gene function in the developing embryo.

The candidate will be involved in one of the two following projects:

Project A:

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments, and is therefore essential for survival. In human, erroneous activation of the pain-sensing system, as in chronic and neuropathic pain, represents a major health burden with insufficient treatment option. New therapeutic options have recently been developed from studies of a small number of individuals with Congenital Insensitivity to Pain (CIP). The majority of these have Mendelelian disorders of painlessness, where disruptive mutations in a single gene are responsible for their inability to sense pain.
Prdm12 has recently been identified as mutated in individuals with CIP (Chen et al., Nature Genet 47, 803-808, 2015). In our laboratory, we have obtained evidence that Prdm12 is crucial for the generation of the nociceptors, the type of neurons that sense noxious stimuli and transfer nociceptive information to the CNS (Nagy et al., Cell Cycle 14, 1799-1808, 2015). Prdm12 belongs to a family of evolutionarily conserved epigenetic regulators that control neuronal specification (Thélie et al., Development 142, 3416-3428, 2015). It is highly and selectively expressed in differentiating nociceptors and remains expressed in these cells post-natally, suggesting that modulating it may be a new route for pain control.
In this project, our aim is to elucidate Prdm12 mechanism of action in nociceptor differentiation during mammalian embryonic development and determine whether its activity also influences nociceptive function in the adulthood. These objectives will be approached through the detailed characterization of Prdm12 null knock-out and transgenic mice and cell lines available or under construction and using state-of-the art genomics, epigenetic, proteomic and electrophysiological approaches.

Projet B:

Understanding the mechanisms that control the generation of distinct types of neurons from multipotent progenitors constitute a major challenge in developmental neurosciences. Transcription factors are at the core of the programs that control cortical development. Two members of the Dmrt family of zinc finger transcription factors, Dmrt3-5, are expressed by cortical progenitors in a similar high caudomedial to low rostrolateral gradient. Our laboratory has shown that Dmrt5, whose mutation in human has been recently associated with microcephaly (Urquhart et al., Clinical Genetics, 2016) is essential for the development of the caudomedial part of the cerebral cortex including the hippocampus and that it plays a direct role in neocortical progenitors in the control of their specification (Saulnier et al., Cereb. Cortex 23, 2552-2567, 2013 ; De Clercq et al., submitted). Recent results of the laboratory indicate that Dmrt3 also contribute to cortical patterning. Despite their importance, the mode of action of Dmrt5 and Dmrt3 in the specification of cortical progenitor identity and in the control of cortical growth remains largely unknown.
In this project, our objective is to understand these mechanisms through the characterization of the phenotype of Dmrt5-/-;Dmrt3-/- double mutant mice and the identification of their in vivo genomic binding sites (using chromatin immunoprecipitation). These studies should provide important insights into the transcriptional mechanisms controling early cortical development.

PhD candidates should be highly motivated and have previous experience in mouse handling, neurobiology or molecular biology. Interested candidates should send their CV including a motivation letter and contact information of at least two previous supervisors able to recommend their research ability to ebellefr@ulb.ac.be

For more information, see our recent work:

Saulnier et al. (2013). The Doublesex Homolog Dmrt5 is Required for the Development of the Caudomedial Cerebral Cortex in Mammals. Cerebral Cortex, 23, 2552-2567.

Nagy V, Cole T, Van Campenhout C, Khoung TM, Leung C, Vermeiren S, Novatchkova M, Wenzel D, Cikes D, Polyansky AA, Kozieradzki I, Meixner A, Bellefroid EJ, Neely GG, Penninger JM. The evolutionarily conserved transcription factor (2015). PRDM12 controls sensory neuron development and pain perception. Cell Cycle. 14, 1799-808.

Thélie et al. (2015). Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus. Development 142, 3416-3428.

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