(This interview by Kathryn Senior originally appeared in Development on July 13)

Thomas Lecuit heads up a multidisciplinary team of 10 scientists at the Developmental Biology Institute of Marseilles (IBDML) in France. He is deeply interested in how the tissues that form our organs acquire and maintain their proper architecture and has special expertise in the physics and modelling of embryonic development. He has been an editor of Development since 2008. Thomas kindly agreed to an interview to tell us about how he got started in science, and about his passion for work, music and sleep…

When did you first realize you were interested in science?

For as long as I can remember, I have always been trying to understand the world around me. I firmly believe that detailed observation and abstraction are essential for understanding. I have a strong memory from when I was 11 or 12 of reading a book about plate tectonics and of being fascinated in how the oceans and continents form. It opened my eyes to the work of scientists and that they can explain phenomena that are far removed from everyday experience. As a kid, I spent a lot of my spare time looking for butterflies and plants, trying to recognize closely related species. I didn’t know that I wanted to be a scientist then, but I realized much later that I was already behaving like one.

Who inspired you to follow a scientific career?

My greatest early mentor was my grandfather. He was a true naturalist, and when I was about 10, he began to educate my sense of observation, teaching me Linnaean classification, focusing on my interest in butterflies. I was lucky that he took my childhood hobby very seriously and helped me rationalize it. I remember him giving me scientific articles about natural butterfly hybrids from the southern Alps, which he had characterized. He also told me about his accidental discovery of a new butterfly phenotype that bred true and that he showed to be due to a dominant mutation. This was extraordinary to me and had a major influence – I think my later career in science owes much to these early experiences.
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Three weeks ago, we joined a group of twenty-four students from around the world arriving in the small town of Woods Hole, Massachusetts. We were strangers from all sorts of backgrounds, but we were drawn together by one commonality – a deep interest in developmental biology. We are all here to participate in the Marine Biological Laboratory’s Embryology course – an intensive six-week program that is in its 116^th year.

The class approaches developmental biology from many perspectives using numerous model and non-model organisms. Each week is structured around a different group of animals, learning the biology and techniques which can be used to study each species, from cnidarians to flies to worms to frogs (and many more!). A typical day starts with a morning lecture presented by a leading scientist, who describes his or her research in the context of the development of the study organism. Following lecture, we have a student driven discussion. Over the years this has come to be known as the “sweat box” because of the probing nature of the questions asked by the students! In the afternoon, lab section begins, and we keep working until late into the night learning new techniques for each organism, as well as using a range of imaging techniques to visualize our results. The students also design and carry out our own research projects, which is the most exciting part of all!

Introduction to each of our research interests:

Laurel Hiebert: I am a second-year graduate student at the Oregon Institute of Marine Biology, University of Oregon, where I am studying the emergence of antero-posterior patterning in a novel larval body plan – the pilidium larva of marine ribbon worms (phylum Nemertea). I have broad interests in evolution of morphological diversity, and I am particularly excited about the opportunity to learn about development in a great variety of organisms.

Sorrel Bickley: I work at the National Institute for Medical Research in London, where I am in the first year of my Ph.D. studying the development of the limbs and the pectoral girdle. I am broadly interested in organogenesis and the processes and pathways that regulate cell differentiation and migration to form a functioning structure. In my lab I work with chick and mouse, so I am excited about the opportunity to try out new techniques in these organisms as well as learning about other species.

Ann Grosse: I am a graduate student in Deborah Gumucio’s lab at the University of Michigan. I study the morphogenetic changes responsible for remodeling the embryonic mouse intestinal epithelium to form a functional absorptive epithelial layer. More generally, my interests include answering embryological and developmental questions of cell polarity, shape, and movement using animal models, live imaging, genetic manipulation, and developmental techniques. Because I will soon be graduating, I am excited to interact and learn from faculty and students who are leaders in their respective fields. Experimentally, I look forward to the animal models most suited for live imaging: C. elegans, Xenopus, zebrafish, and sea urchin.

We will update this blog each week to discuss the work we have been doing on the course and also to show some of the images we have captured. As an introduction we would like to share this beautiful grasshopper embryo image, which was stained with an Ultrabithorax antibody (in red) and DAPI (in blue). We are very thankful to the Company of Biologists, who provided scholarship funds for the three of us.

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The Node has been officially live for almost four weeks now, and we’ve seen visitor numbers and registrations go steadily up. As with most websites, there are far more silent readers than people who are actively writing, so here are a few tips on keeping up to date with the Node:

If you don’t want to miss a single post, the easiest thing to do is sign up for our e-mail alerts. They currently go out once a day if there was at least one new post that day. If you are a registered user of the Node, you can also change your e-mail settings to only receive certain categories. For example, if you just want to read news and no interviews, or only want meeting reports and don’t care about career posts, you can customize all that, so you’re  only sent the information that you’re interested in.

Another way to read the Node is by RSS. Not everyone we talked to knows how to use this, so here’s a brief explanation: RSS feeds are a useful way to keep track of sites that update regularly, such as blogs or scientific journals or news websites. (The best explanation of RSS is probably this video). Websites that have an RSS feed will usually have a little icon like the one pictured here somewhere on the site, or next to the url in your browser’s address bar. To read RSS feeds, you need a feed reader. Google has one that’s free to use from within your web browser (so you don’t need to download anything). It works a bit like an e-mail program: every time you visit your feed reader, you’ll see which websites have updated since you last looked. Most journals use RSS feeds as well, and the four table of contents that we show in the Node sidebar to the right are in fact the RSS feeds of these journals. If you follow a lot of regularly updated websites (journals, blogs, the Node, news websites) and don’t want their updates to clutter your e-mail inbox, give it a try! The Node has feeds for some subsections of the site as well as a feed for everything, so you can pick what you want to read from our RSS page.

Finally, you can of course still visit the Node website the old fashioned way. In fact, you’re getting a lot more out of it if you do! You can see the list of events, use the links in the sidebar, see the journal table of contents, read people’s comments, and if you feel like it, you can leave a comment yourself: Anyone can comment on the Node, even without an account, but we do ask that you fill out your e-mail address. Leaving your e-mail address is just a safety measure to prevent abuse of the comment feature, and the address is not displayed on the site.

If you have any other questions about reading the Node, let us know, either in the comments or via e-mail.

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Here are the research highlights from the new issue of Development…

TORc1-ing about stem cell differentiation

In adult tissues, the tight regulation of stem cell selfrenewal and differentiation maintains tissue homeostasis. In Drosophila ovaries, BMP signalling from the local environment maintains germline stem cells (GSCs) by repressing bam (a differentiation-promoting gene) expression. Now, on p. 2461, Rongwen Xi and co-workers reveal a role for the tumour suppressor tuberous sclerosis complex proteins, TSC1/2, in GSC maintenance. Human TSC1 and TSC2 proteins form a complex that negatively regulates TOR, a conserved kinase involved in cell growth. TOR functions mainly via the TORC1 complex, which activates the protein translation initiator S6K. Disruption of Tsc1 or Tsc2 in Drosophila GSCs, the researchers report, leads to precocious GSC differentiation and loss. Elimination of S6K rescues this phenotype, which implicates TORC1 hyperactivation in the precocious differentiation of Tsc1/2 mutant GSCs. TORC1 hyperactivation also negatively regulates BMP signalling. Thus, suggest the researchers, TSC1/2-TORC1 signalling maintains Drosophila GSCs by controlling both BMP-Bam-dependent and -independent differentiation programs, a role that might be conserved in mammals.

Olfactory neuronal precursors sniffed out

Neuronal precursors in the developing olfactory epithelium (OE) produce olfactory receptor, vomeronasal and gonadotropinreleasing hormone neurons, neuronal classes that are essential for chemosensation, social interactions and reproduction. Now, Anthony-Samuel LaMantia and colleagues characterise two distinct populations of neuronal precursors in the mouse OE that give rise to these neuronal types (see p. 2471). They describe a population of slowly dividing, self-renewing precursors mainly in the lateral OE that express high levels of Meis transcription factors and a population of rapidly dividing neurogenic precursors mainly in the medial OE that express high levels of the Sox2 and Ascl1 transcription factors. The Meis dose in the first population reduces Ascl1 expression and neurogenesis, they report, whereas the Sox2 dose in the second population, which is partly controlled by local Fgf8 signalling, promotes OE neurogenesis by suppressing Meis1 and enhancing Ascl1 expression. These insights into the characteristics of OE neuronal precursors should facilitate the identification of the adult OE neural stem cells that generate olfactory receptor and vomeronasal neurons throughout life.

Ringing the changes on bivalent gene silencing

In pluripotent ES cells, key developmental regulators contain ‘bivalent chromatin domains’ – regions that carry epigenetic markers of both repressed and active chromatin, and that assemble RNA polymerase (RNAP) complexes. Thus, these bivalent domains silence genes, but keep them primed for timely activation and are thought to resolve into repressed or active domains upon ES cell differentiation. But are bivalent chromatin domains involved in in vivo development? On p. 2483, Véronique Azuara and colleagues report that these domains operate in the early mouse embryo. They show that several somatic lineage regulators (including Hox factors) retain bivalent chromatin domains in cells that are committed to the extra-embryonic lineage. However, these genes, in contrast to similar genes in pluripotent cells, are not engaged by the Polycomb repressive complex component Ring1B. Instead, these bivalent genes are selectively targeted for Suv39h1-mediated repression through H3K9 methylation, and for RNAP exclusion upon trophoblast lineage commitment. Thus, Ring1B and Suv39h1 play mutually exclusive roles in the establishment of distinct chromatin states during early mouse lineage commitment.

On PAR1 spindle orientation promotes neurogenesis

In the developing vertebrate CNS, ‘deep’ cells differentiate into neurons whereas undifferentiated superficial epithelial cells continue to proliferate. The rate of neuronal differentiation depends on the balance between these two cell types, which are generated by asymmetric divisions of the superficial cells. Now, Jeremy Green and co-workers reveal that the conserved polarity protein PAR-1 promotes these asymmetric divisions in the neural plate of Xenopus embryos by controlling spindle orientation (see p. 2501). PAR-1, which is basolaterally localised in epithelia, is required for the differentiation of deep cells. By grafting marked superficial cells that express activated PAR-1 onto untreated embryos, the researchers show that PAR-1 drives the generation of deep cells from the superficial epithelium. Depletion experiments indicate that PAR-1 is normally required for vertically orientating epithelial mitotic spindles, thereby ensuring a sufficient number of asymmetric cleavages. Importantly, the effect of PAR-1 on spindle orientation not only generates deep cells, note the researchers, but also promotes neurogenesis by partitioning these cells away from anti-neurogenic, apically localised atypical protein kinase C.

Ectodermin damps down Nodal

During early vertebrate embryogenesis, gradients of the TGFβ-related factor Nodal control embryonic pluripotency and establish the body plan. But how do embryonic cells interpret subtle changes in Nodal signalling? According to Stefano Piccolo and colleagues, the negative intracellular Smad regulator ectodermin (Ecto) determines how mouse embryonic cells read Nodal signals in vivo (see p. 2571). Recent results suggest that the ubiquitin ligase ectodermin acts as an intracellular regulator of TGFβ signalling by monoubiquitylating Smad4, which causes the disassembly of the R-Smad/Smad4 transcriptional complex that mediates TGFβ signalling. Here, the researchers show that ablation of Ecto in trophoblast cells disrupts the balance between stem cell self-renewal and differentiation by increasing their Nodal responsiveness, a result that reveals a new role for Nodal signalling in trophoblast development. In the epiblast, they report, Ecto deficiency shifts mesoderm fates towards node/organiser fates. These and other results suggest that the negative control of Smad activity by ectodermin orchestrates early mouse development by ‘tuning’ the responses of extra-embryonic and embryonic cells to Nodal.

Polycomb recruitment to DNA: Spps enlisted

Polycomb group (PcG) protein complexes repress gene expression during the development of higher eukaryotes by binding to Polycomb group response elements (PREs). Little is known about how PcG complexes are recruited to PREs but, on p. 2597, Lesley Brown and Judith Kassis suggest that Spps (Sp1-like factor for Pairing Sensitivesilencing) might be involved in this process in Drosophila. All known Drosophila PREs contain binding sites for Sp1/KLF zinc-finger proteins. The researchers now report that the Sp1/KLF family member Spps binds to Ubx and engrailed PREs, and to polytene chromosomes in a binding pattern that closely matches that of the PcG protein Psc. Spps deletion suppresses ‘pairing-sensitive silencing’, they report, a PRE-associated activity in which somatic-chromosome pairing increases PcG-mediated repression. Spps mutation also enhances the phenotype of pho mutants; the PcG protein Pho is involved in, but not sufficient for, PcG complex recruitment to PREs. Together, these results suggest that Spps works with, or in parallel to, Pho to recruit PcG complexes to PREs.

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Here is the final part of my meeting report on the BSDB-BSCB Spring Conference this April in Warwick. In the first part, I covered some of the talks on transcriptional regulation, and in part two I gave a brief overview on recent attempts to decipher large-scale transcription factor networks. In this final part I will touch on several seemingly unrelated subjects, which reflects how difficult it was for us developmental biologists to make choices between some of the parallel sessions: the BSCB’s stem cell sessions and the BSDB’s limb development and “evo-devo” sessions.

In one of the stem cell sessions, Austin Smith (Centre for Stem Cell Research, Cambridge, UK) emphasized the artificial nature of cultured embryonic stem (ES) cells and how the previously empirically determined requirements to maintain these cells do not reflect minimal requirements. Supply of these factors, such as specific sera, might even be counterproductive in maintaining the pluripotent state, since they contain many inductive stimuli. His lab has established that specific inhibition of the MEK/ERK cascade and GSK3 simultaneously is sufficient to provide optimal conditions for ES cell derivation and maintenance from all mouse strains and even from rats.

Kevin Eggan (Harvard University, USA) and his group have succeeded in reprogramming skin cells of patients suffering from either inherited or sporadic instances of Amyotrophic Lateral Sclerosis (ALS) into pluripotent stem cells. They were then able to differentiate these patient-specific induced pluripotent stem (iPS) cells into spinal motor neurons and glia, the cell types affected in the disease. Now they are comparing the behavior of these cells to that of the corresponding cell types generated from skin cells of healthy individuals, attempting to uncover the molecular mechanisms underlying ALS.

Of the limb development session I will only cover Richard Behringer‘s (University of Texas, Houston, USA) talk, since I did a bit of session hopping at that time. He presented their work on forelimb development in the bat, where they identified Paired-related homeobox 1 (Prx1) as a promising candidate underlying limb diversification between mouse and bat. In mice, they replaced the Prx1 enhancer with that of the bat, and observed a significant increase in both the length of the forelimb and the levels of Prx1 mRNA. In the second part of his talk, Behringer described their experiments in which they expressed a human HoxB1-9 transgene in a HoxB1-9 knockout mouse. This resulted in almost complete rescue of the knockout phenotype. Interestingly, the presence of the human transgene had a dominant effect in either wildtype or mutant mice: Only 5 sacral vertebrae rather than 6 formed, which might be the result of a shift of the expression boundary of HOXB9 in human compared to the mouse.

After first making a case for the need of new model organisms by presenting his group’s work on germline formation in the beach hopper Parhyale hawaiensis, Nipam Patel (University of California, Berkeley, USA) described how he has been using Google’s search engine to collect about 3000 examples of mosaic butterfly gynandromorphs, which show regions of both male and female characteristic patterns in the same wing. He observed that these naturally occurring clones do not cross a certain boundary, which is distinct from the boundary separating the classical anterior and posterior compartments defined in Drosophila. They were able to experimentally trace the origin of this unexpected compartment back to embryonic development. This so-called S compartment is also present in Drosophila, albeit in a very thin line. The studies Patel presented demonstrated how much there still is to learn in developmental evolution, and how the usage of unconventional model organisms can unmask unknown processes, which might be more concealed in our traditional systems.

Kristin Tessmar-Raible (University of Vienna, Austria) presented the unusual organism and topic her team works on: They use the annelid worm Platynereis dumerilii to study lunar rhythms, which synchronize spawning in these animals. In a series of experiments using entrainment and expression profiling of candidate genes, they identified the core set of genes of the lunar clock. Interestingly, the circadian and lunar clocks seem to regulate the same subsets of genes. A group of photosensory-neurosecretory cells of the inner medial forebrain of this species has recently been shown to represent the ancient core of vertebrate and invertebrate brains, and Tessmar-Raible’s group is now investigating whether and how these cells are involved in regulating the clocks.

Finally I’d like to mention the BSDB’s Waddington Medal, which is awarded annually at the spring meeting to a developmental biologist for their outstanding research performance and services to the subject community. This year it went to Robin Lovell-Badge (NIMR, London, UK), for his research on sex determination, stem cells and the development of the nervous system. He gave a highly entertaining lecture on the important steps in his life and career, including video coverage from his childhood and pictures of the various cars he has owned over the years.

I thoroughly enjoyed the meeting, especially due to the wide range of subjects it covered. So I’m looking forward to attending next year’s spring meeting, which will be announced here.

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Does anyone know a protocol for rehydrating embryos once stored in methanol?  I’m working with Xenopus laevis embryos which have been fixed using formaldehyde.  Some lab wisdom passed down is “wash into a 50:50 solution of 1xPBS and methanol; then into 1xPBS; then into methanol again (which we’re a bit confused by); then into 50:50 PBS: methanol; and finally 1xPBS”.

Any help would be much appreciated!

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Yes, we’ve been live for a few weeks, but you’re not truly and fully launched as a website these days without a proper launch party, so we had ours last night in Cambridge (UK).

The Gurdon Institute was kind enough to open their doors to us, and we invited all of their labs as well as other local developmental biologists to join The Company of Biologists and Development for some celebratory champagne and canapés. We were also joined by representatives from the Journal of Cell Science, Nature Cell Biology, PLoS Biology, F1000/The Scientist, and Nature Network Cambridge.

With the Node projected on screen, and three laptops available to browse the site, we had a unique chance to show people around the site in person, and got some useful feedback and suggestions as well.

Several people registered on the Node during or after last night’s event. Welcome! We hope you (and all other new registrants) will use the Node to read and share, and that you had a good time yesterday!

Now the party is over, the leftover canapés have been consumed by our colleagues back at the office, and it’s back to regularly scheduled Node posting and reading. The sad thing about launching is that you can do it only once!

The Company of Biologists’ publisher Claire Moulton, with Company directors and Cambridge researchers John Gurdon and Daniel St Johnston.

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Using light microscopy to study developmental processes in situ is a bit tricky if your samples are not transparent. In that aspect, early zebrafish development is a walk in the park compared to studying non-transparent fly embryos, or even fish in a later stage of development.

But research published in Nature Methods this week comes with a solution. Thanks to Philipp Keller and his colleagues, it’s now possible to take very clear images of non-transparent samples, such as Drosophila embryos, or to monitor zebrafish development much longer – up to three days. This has produced a database of detailed images and movies of Drosophila embryo development.

A few years ago, the group developed a technique called digital scanned laser light sheet fluorescence microscopy (DSLM), in which a laser beam illuminates a slice of the sample, and a detector records fluorescence of just that slice. But that produced a very noisy signal in the presence of many refractive cell membranes – in other words, with non-transparent samples. To solve this problem, they changed the laser beam properties: Instead of a continuous beam of light, the signal was pulsed. By combining multiple pulsed images of the same section, the signal and noise were easier to distinguish, which led to a much clearer image.

How clear exactly? To test the new system (DSLM-SI), Keller monitored zebrafish development up to three days. Compared to studies done with traditional methods, he could see far more detail, including eye and midbrain development. When using DSLM-SI, they were also able to collect very detailed information of cell positions over time in a Drosophila embryo, and combined this information into a dataset with 1.5 nucleus data entries. You can see the resulting dataset, images, and movies on the digital embryo website.

Fore more information, see the EMBL press release, or the original paper.

(image via EMBL, courtesy of Philipp Keller and EMBL.)

(Read an interesting paper about developmental biology lately? Let us know on the Node!)

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Almost four thousand people attended the International Society for Stem Cell Research (ISSCR) meeting in San Francisco in June. According to the San Francisco Chronicle, about a quarter of the attendees were from California, but other participants traveled from Australia, Europe, and Asia to attend the meeting. There were far too many talks to summarize the entire event, but Development’s new Reviews Editor, Seema Grewal, and I have selected some of the ones that we thought you might find interesting. Where we found a published paper related to the same topic, we’ve linked to the PubMed abstract, so you can look up more information.

Unfortunately (due to a late flight!) we missed the entire first day of the conference, but if you were there, please let us know what you thought of the talks on that day!
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Ahhh the Node, my favourite part of the embryo: nice cup shape you can lie back in and get a whirly cilia massage…. OK, on with the post.

So it seems that everyone is working on stem cells now. They’re all the rage. Students come through for a rotation and ask “do you work on stem cells?”, grants with some aim that includes stem cells seem to do better than regular dev bio grants, and of course the papers….well the papers speak for themselves. But is this such a surprise and does this have any bearing on those of us who study embryonic development but haven’t cultured a stem cell other than maybe to make a knockout mouse? The answer is that it depends what you care to study, and whether you care if there is a difference between the two.

Because really stem cell biology is but an integral part of developmental biology. Stem cells, especially the non-cultured variety, are a normal part of embryonic development (or in the case of cancer stem cells, a rather unfortunate return). Isolating and culturing these stem cells is really figuring out how to freeze them in that transient state. In fact one might as well call development embryonic stem cell allocation (or something more clever). Most of you don’t need convincing, as many of the giants in stem cell biology were first giants in developmental biology (Rossant, Melton, Martin, Keller, and so on), and they simply applied the principles of embryology that they had developed to isolate the specific cell types that do their thing in the embryo. Not really simple, but you get the point.

When there were no stem cell journals, papers on stem cells or progenitors were published in development journals. Now of course we still have developmental biology journals, but a flurry of stem cell-specific journals have appeared, some bearing influential imprints, and these have done very well. I do however like the new trend, espoused recently by Development, of enthusiastically marrying back the two fields, like a happy homecoming or two good friends who parted ways years ago. It’s natural, it makes sense, and it certainly fits with what is hot right now in stem cell biology, which is helping stem cells find a path to a particular lineage and coax them become the cell type you wish to have in the dish. Sound familiar? Indeed the reverse trend is also taking place, with the stem cell journals publishing papers with a very developmental angle.

Of course the promise of therapeutics that stem cells bring distinguishes part of that field from developmental biology, but that’s the reason for it, often not the actual research that goes behind it. (Although the irony is that perhaps developmental biology’s fruits will severely diminish the therapeutic potential of stem cells: who needs the chance of a teratoma when you can just reprogram that skin cell straight into a nice neuron? )

So good friends meet again, hang out for a while, get to know each other again. As stem cell biology advances along lineage paths, and developmental biology takes a dip in the stem cell pool, we will do this with the comforting thought that we’re all doing the same thing: discovering where we come from and how we got here.

(7 votes)

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