Here are the highlights from the current issue of Development:

How transcriptional silencing goes into reverse

The Polycomb group (PcG) machinery silences terminal differentiation genes in stem cell lineages. Reversal of this epigenetic transcriptional silencing is implicated in the selective activation of these genes during differentiation, but little is known about the mechanism of this process. To find out more, Xin Chen, Margaret Fuller and colleagues have been examining the reversal of silencing in the Drosophila male germline stem cell (GSC) lineage. They report that developmentally regulated sequential events at promoters relieve the silenced state of the GSCs when their offspring commit to spermatocyte differentiation (see p. 2441). These sequential changes include the global downregulation of Polycomb repressive complex 2, the recruitment of hypophosphorylated RNA polymerase II to promoters, the expression and function of testis-specific homologues of TATA-binding protein-associated factors, and the function of the testis-specific meiotic arrest complex. These results provide a paradigm for how epigenetic silencing can be reversed in a gene-selective and stage-specific manner to allow the appropriate expression of terminal differentiation genes.

β-Catenin degraded by Notch in early frog development

In vertebrates, the Wnt/β-catenin pathway is the core of a conserved mechanism that establishes the main body axis during early development. Now, on p. 2567, Andrés Carrasco and colleagues report that Notch restricts dorsal-anterior development in Xenopus by destabilising maternal β-catenin. The blastula chordin– and noggin-expressing centre (BCNE) is a signalling centre in early Xenopus embryos that precedes the Spemann-Mangold’s organiser and that contains brain precursors. BCNE specification depends on the dorsal accumulation of nuclear β-catenin. By injecting early embryos with Notch mRNA and morpholino constructs, the researchers show that Notch antagonises Wnt signalling by degrading β-catenin in the ventral region of the embryo. This degradation process, they report, does not require β-catenin phosphorylation by GSK3, a process that usually marks β-catenin for degradation. The researchers suggest that this interaction between Notch and β-catenin, which has not previously been recognised in vertebrates, restricts the size of the BCNE and controls the size of the brain.

Mon2 takes pole (plasm) position

In Drosophila oocytes, the pole (germ) plasm, a specialised cytoplasm at the oocyte posterior, contains the maternal RNAs and proteins that are essential for germline and abdominal development. Akira Nakamura and co-workers now describe the role that the Golgi-endosomal protein Mon2 plays in pole plasm anchoring (see p. 2523). Pole plasm assembly begins with the transport of oskar (osk) RNA to the oocyte posterior where it is translated. Osk then stimulates endocytosis, which promotes an actin remodelling event that is essential for pole plasm anchoring. The researchers report that Mon2 interacts with Cappuccino and Spire, actin nucleators involved in osk RNA localisation in the oocyte, and promotes the accumulation of the small GTPase Rho1 at the oocyte posterior. In oocytes lacking Mon2, actin remodelling does not occur in response to Osk-induced endocytosis and pole plasm components are not correctly anchored. The researchers propose, therefore, that Mon2 is a scaffold that links Osk-induced vesicles with actin regulators to anchor the pole plasm to the oocyte cortex.

RanBPM – a scaffold for gametogenesis

The recently identified scaffold protein RanBPM belongs to the Ran-binding protein family. Like other scaffold proteins, RanBPM interacts with numerous proteins, but what is its function? Lino Tessarollo and co-workers now report that RanBPM is essential for mouse gametogenesis (see p. 2511). Using gene targeting, the researchers show that adult RanBPM^−/− mice of both genders are sterile and have atrophied gonads. They report that in male RanBPM^−/− mice the testes develop normally for one week postnatally but that there is then a marked decrease in spermatogonia proliferation. The first wave of spermatogenesis, they report, is characterised by spermatocyte apoptosis towards the end of prophase I. Moreover, experiments in chimeric mice indicate that RanBPM acts in a cell-autonomous way in male germ cells. Finally, they show that fertility in female RanBPM^−/− mice is compromised because of germ cell depletion at the end of prophase I. Thus, mammalian RanBPM plays a crucial role in both spermatogenesis and oogenesis.

Gli-ful insights into Hedgehog signalling conservation

Hedgehog (Hh) signalling controls cell fates and cell proliferation in many animals by regulating gene transcription. Some parts of the Hh pathway, including the final transcriptional effectors, are highly conserved. Thus, in flies and mammals, Hh signalling activates full-length Cubitus interruptus (Ci) and Gli family transcription factors, respectively, and prevents Ci/Gli proteolytic processing to repressor forms. But, are the molecules that regulate Ci/Gli protein activities similarly conserved? Steven Marks and Daniel Kalderon address this contentious topic on p. 2533 by investigating the regulation of mammalian Gli proteins in Drosophila cells. They show that the fly kinesin-family protein Costal 2 (Cos2), which directs Ci processing in Drosophila, binds to three regions of the transcriptional activator Gli1, just as for Ci, and that Cos2 silences mammalian Gli1 in Drosophila cells in an Hh-regulated manner. They also show that Gli regulation by protein kinase A is conserved between flies and mammals. Together, these results reveal a greater degree of Hh pathway conservation than was previously recognised.

POU proteins: ancient stem cell regulators

What is the evolutionary origin of pluripotent stem cells? On p. 2429, Uri Frank and colleagues provide new insights into this longstanding question by studying the marine cnidarian Hydractinia echinata. In mammals, pluripotent stem cells are limited to early embryos where they are induced and maintained by the POU domain protein Oct4 and certain other key transcription factors. By contrast, clonal invertebrates such as H. echinata possess pluripotent stem cells throughout their life. Here, Frank and colleagues report that Polynem (Pln), a putative homologue of Oct4, is expressed in the embryonic and adult stem cells of H. echinata and that ectopic expression of Pln in epithelial cells induces stem cell neoplasms and loss of epithelial tissue. Neoplasm cells, they report, downregulate expression of the Pln transgene but express the endogenous Pln gene and other cnidarian stem cell markers. Conversely, Pln downregulation by RNAi leads to differentiation of adult stem cells. Together, these results suggest that POU proteins are conserved regulators of stem cells.

Plus…

Recent evidence suggests that craniofacial muscles are evolutionarily, morphologically and molecularly distinct from those of the trunk. Here, Sambasivan, Kuratani and Tajbakhsh review these studies and discuss the molecular basis of craniofacial muscle development.
See the Review article on p. 2401

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Hi there! My name is Melinda, and I’m a postdoctoral researcher at Cambridge University in the UK in the lab of Dr. Clare Baker (http://www.pdn.cam.ac.uk/staff/baker/). I’ve just wrapped up my research trip to work on paddlefish embryos in the southeastern state of Georgia in the United States, generously funding by the Development Travelling Fellowship award!

We are used to experiencing the world with five senses: sight, smell, taste, touch, and hearing. Many of these sensory systems are generated by placodes, which are regions of thickened ectoderm found in the embryonic head that generate a variety of peripheral sense organs, such as the otic and olfactory placodes, which form the inner ear and nasal epithelium, important for hearing and smelling, respectively. Hearing and balance are mediated by the mechanical displacement of tiny ¨hairs¨ on specialized sensory ¨hair cells¨ in our inner ears (also simply called mechanoreceptors).  In fish and aquatic amphibians, a series of lateral line placodes generates the lateral line system, which also contains modified mechanoreceptor hair cells, much like those found in the inner ear. These are used to detect changes in the local water environment important for prey or predator detection and schooling behaviors. In addition to the mechanoreceptors, another type of modified hair cell can be found in all major aquatic vertebrate groups: these are the electroreceptors, distributed in fields of “ampullary organs” on either side of the lateral lines of mechanosensory hair cells.

As the name suggests, electroreceptors allow animals that possess them to detect weak electric fields in water. Similar to mechanoreceptors, this is also used to find prey and for orientation. However land vertebrates (including reptiles, birds and mammals), as well as frogs and most modern bony fish (such as teleosts), have lost this ancient ¨sixth sense¨. They are still found in many aquatic vertebrates including jawless fish (lampreys), cartilaginous fish (sharks, rays), primitive bony fish (e.g. sturgeon, paddlefish), and even some amphibians (salamanders). Interestingly, in a few groups of modern bony fish, such as catfish and “electric fish”, electroreceptors have been independently “re-invented”. Although an evolutionarily ancient sense, electroreceptors were only discovered in the 1950s, and very little is known about their development or formation, i.e., how they develop in the embryo, what genes control their development, and what makes the difference between the sensory hair cells that detect changes in electric fields and those that detect water movement.

That’s where the North American paddlefish (Polyodon spathula) can help! This is truly an incredible animal. It has the most electroreceptors of any living vertebrate: between 50,000 and 70,000 “ampullary organs” per adult, many of them located on their rostrum or “paddle”, which is an extension of their cranium that accounts for nearly a third of their total body length (typically 1-2 meters).  Although a vulnerable or “threatened” species, conservation and farming efforts have made this primitive fish commercially viable as a source of caviar (No, I’ve never tried it…maybe it’s just me, but I’m not crazy about the idea of eating what I study), thus allowing us to obtain embryos for studying hair cell, and more specifically, electroreceptor development.

Now, contrary to what people initially think about my “field” trips, I don’t even see the adult fish! I go to the lab of collaborator Marcus Davis at Kennesaw State University, which is located on the outskirts of Atlanta, Georgia. The actual process of fertilizing the embryos is done in Missouri at Osage Catfishieries (osagecatfisheries.com) by the Kahrs family, a terrific family owned business that we’ve worked with over the years. Fertilization is external, so mature adults are injected with hormones that, along with weather conditions, dictate whether they are ready to be squeezed  (or in the case of males “milked” for sperm). So like buying from Amazon, I get an approximate delivery date and anxiously wait until I get an email saying the box of embryos is on the way. Once there, our game faces come on and, it’s at least 14 days of working all kinds of hours to ensure we maximize the one or two clutches we get per year. That means all experimental manipulations (e.g. injections, electroporations, drug treatments) need to be done in a short amount of time, in addition to the husbandry and collection of fixed specimens for future work. To say it´s intense at times is an understatement.

For me, one of the biggest challenges working at this university is that they are still in “transition” from their previous role as a small two-year college to a large four-year undergraduate college trying to advance scientific research. To give you an idea of what this means, there are no graduate students or postdocs, and I am the first postdoctoral researcher to ever visit this department. While I do get to interact with other faculty and undergraduate students, for the most part, I work alone. While I appreciate the chance to get caught up on all the podcasts I let pile up, it’s a very different environment to what I’m familiar with. Also as a former “commuter” school, it is located just off the major interstate, convenient for drivers, but not close to town. So any excursions require driving, thus making it more difficult to explore the area when you are limited for time.

However, two of my favorite things about going to Georgia (besides working on paddlefish, of course) are southern food and spring thunderstorms. Coming from England, I know drizzling rain. But in Georgia, with little warning, thunder and lightening just roll in. It can be quite a show and then 15 minutes later it’s completely gone and if it’s still daylight, the sun comes back out. Usually, it’s no big deal and quite normal around here. This year was different though. Across much of the southern United States, many states experienced the worst storms and tornados in nearly four decades! Luckily, the area I was visiting was spared much of the destruction: we only had a couple of power outages, but it did make for a few sleepless nights. All in all, not a bad season.

To see a juvenile paddlefish eating, check out this video I took:

(8 votes)

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Sophie Pryor

Institute of Child Health

University College London

The third Young Embryologist Meeting, which brings together PhD students, Post-Doctoral and Young PI researchers, was held on Friday 6^th May at King’s College, London. The meeting was initially established in 2008 by PhD students and Dr Yoshiyuki Yamamoto from the UCL Research Department of Cell and Developmental Biology (CDB), and is now organized and run by the Young Embryologist Network, a group of PhD students and Post-Docs from four London departments (UCL Dept. of CDB, Institute of Child Health, NIMR and Kings College London). The Young Embryologist Meeting is the main event organised by The Network, and aims to promote interaction and collaborations between early career researchers working on a variety of models and developmental systems. This year’s 130+ audience was comprised of researchers from 18 institutions (15 in the UK and 3 abroad).

The meeting opened with a keynote lecture by Prof. Sir John Gurdon, of the Gurdon Institute at the University of Cambridge, who is described on the Wellcome Trust’s website as ‘the man who made cloning possible, pioneering nuclear transfer and the ‘reprogramming’ of the fate of cells’. Prof. Gurdon spoke about the different methods of nuclear reprogramming, explaining the advantages of transplanting somatic nuclei into host oocytes (defined as those at the first meiotic prophase), rather than into eggs (those at second meiotic metaphase). He went on to discuss the mechanisms of nuclear reprogramming, namely: 1) the removal of differentiation markers, 2) chromatin de-condensation and protein:DNA exchange, 3) transcription activation and 4) the resistance of somatic cells to reprogramming as they become increasingly specialised. In conclusion, Prof. Gurdon described the emergence of a ‘time course’, saying that ‘the earlier you go back (towards pluripotency) the wider the reprogramming’.

The first session of the day, entitled ‘Organogenesis’, was made up of five talks on topics ranging from eye formation in the fruit fly to the genetics of mammalian cardiovascular development. The first speaker was Holger Apitz (NIMR), who presented his research into a novel mode of neurogenesis in the inner proliferation centre (IPC) of the Drosophila optic lobe. Holger discussed the identification of a new allele of Polycomblike (Pcl), which he has found to be involved in the specification and maintenance of outer (OPC) vs IPC neuroepithelial cell identity, regulation of EMT in subdomains of the IPC, and in preventing the premature differentiation of migrating progenitors into neuroblasts. Kenzo Ivanovitch (Dept. of CDB, UCL) showed fluorescent time lapse movies from his work on the division of the zebrafish eye field into two laterally located optic vesicles, and discussed the mechanism by which eye field cells acquire their polarity during this process. Lucy Freem (Institute of Child Health, UCL) spoke about the role of the Sox10 transcription factor in the formation of neural crest-derived intrinsic neurons during mammalian lung development, as well as describing the abnormal lung innervation in the Tbx1 mutant mouse. Divya Venkatesh (Institute of Genetic Medicine, Newcastle) discussed the development of the aortic arch arteries and her characterisation of the cardiovascular abnormalities in Pax9-null mice, which recapitulate human congenital heart defects. Closing the session was Andrew Economou (King’s College), who used mathematical simulations to describe his work on the role of Shh and Fgf signalling during formation of the regularly spaced ridges, or ‘rugae’ in the mammalian palate.

The second session consisted of four talks on different aspects of ‘Signalling and Epigenetics’. Ohad Shaham (Tel Aviv University, Israel) spoke about the function of Pax6 during eye development and his work to uncover novel roles of the transcription factor in cell cycle exit, lens epithelial cell survival and lens fibre cell differentiation in mouse embryos. He also discussed the results of his microarray analysis, which uncovered a high number of Notch pathway-related genes which are negatively regulated by Pax6. Characterisation of the Xenopus histone variant isoforms H2A.Z1 and H2A.Z2 was the subject of Jordan Price’s (University of Portsmouth) talk, where he presented the morphological and paralysis phenotypes produced by knockdown of each of these isoforms, respectively. Richard Wells (Sheffield University) discussed his research into the role of the JAK/STAT cytokine pathway in the Drosophila embryonic hindgut, which provides a valuable model to study the acquisition of left-right asymmetry during organogenesis. He showed that asymmetrical JAK/STAT signalling regulates gut curvature by controlling tissue stability via the localisation of Fascillin III. Last to speak was Paula Alexandre (King’s College), who reported on neuronal differentiation in the zebrafish brain and proposed a model, involving the dynamic remodelling of cellular protrusions, to explain neuronal spacing in the spinal cord.

The lunchtime poster session was followed by three talks on the subject of ‘Evo-Devo’. Adrien Demilly (Institut Jacques Monod, Paris) addressed the uncertainty surrounding the timing of CNS and neurogenesis evolution by describing the neurectoderm architecture in the annelid marine worm Platynereis dumerilii. In particular, he discussed the possible involvement of Wnt signalling in an organising centre at the ventral midline. The evolution of cerebellar development was discussed by Thomas Butts (King’s College), who described how species variation in cerebellar structure is largely due to variations in granule neuron progenitor (GNP) proliferation patterns. He presented a model whereby the successive evolution of GNP transit amplification explains the complexity of the amniote cerebellum. The final speaker, Dorit Hockman (Cambridge University), spoke about the different embryonic origins of oxygen-sensing cells in the carotid body and lung airway epithelia, before describing her work to identify the signalling pathways required for the specification of O₂-sensing cell fate.

The day concluded with a lively careers question and answer session by Prof. Claudio Stern (Dept. of CDB, UCL), Prof. Jon Clarke (King’s college) and Dr Claudia Linker (King’s College). One audience member asked the three PIs what qualities they would look for when hiring a post-doc. Prof. Clarke said he tries to find those with a ‘genuine interest’ who have the ability to ‘present their research well, ask sensible questions and are capable of generating their own ideas’. He also spoke of his amazement at how many people come to visit his lab without doing any preparatory reading about the research that goes on there! Another question was: ‘How important is it to do a post-doc abroad?’ Prof. Stern stressed that the important thing is to find a good lab and spoke of the benefits of change and increasing the breadth of your research. Dr Linker described her own experience of working with different model systems, saying that ‘moving around is good for you and your cv’. The panel members were also asked what had been their hardest career moment, to which Prof. Clarke answered ‘knowing when to go for your first PI position’. Prof. Stern described the challenge of being successful at highly competitive interviews, and also voiced concerns about the effect that current government cuts to research funding would have on those looking for jobs in the future. He advised the audience that ‘if you’re convinced you want to do science, just go for it!’

The day was a great success and allowed young embryologists to present their research in a relaxed environment. The lunchtime poster session and evening wine reception provided the opportunity for attendees to discuss other people’s work and exchange ideas about many aspects of developmental biology. Congratulations to Dorit Hockman (Cambridge University) and Andrew Economou (Kings College London), who were awarded first and second prize respectively for best talks of the day and to Ricardo Laranjeiro (University College London) and Emily Hoggar (University of Sheffield) who were awarded first and second poster prizes, respectively.

For more information about the Young Embryologist Network, please see the website (http://www.ucl.ac.uk/cdb/yen) or find us on Facebook.

(7 votes)

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I am now a Patent Attorney at Clark & Elbing, a Boston boutique patent law firm specializing in biotechnology and pharmaceuticals. I have been at Clark & Elbing since 1998, and am now a partner.

Prior to becoming a Patent Attorney, I was a graduate student in Connie Cepko’s laboratory at Harvard Medical School. For my research, I studied intrinsic and extrinsic cell fate choices in the developing vertebrate retina. Even prior to attending graduate school, I had been interested in retinal development; during my undergraduate career, I worked in a laboratory studying development of the retina in teleost fish.

My time in the Cepko lab was fun and fulfilling. During my time there, several exciting discoveries were made by other lab members, including identification of a photoreceptor-specific transcription factor as well as several other genes assymetrically expressed in the developing retina. Additionally, we shared lab space and lab meeting with the members of Cliff Tabin’s lab. It was at this time that Cliff and his colleagues identified the Sonic Hedgehog gene.

I had been interested in patent law even before attending graduate school. Prior to attending Harvard, I had taken the LSAT law school admission examination. From discussions with patent attorneys, I learned that completion of a Ph.D. was nearly an essential requirement, so I delayed law school and instead pursued my doctorate degree.

During my final months in the Cepko lab, I explored the possibility of joining another lab as a post-doc. I interviewed in several prominent developmental neurobiology labs and was offered a position in each of them. In the end, my heart wasn’t completely committed to continuing with scientific research, and I chose to resume my pursuit of a career in law.

Fortuitously for me, Connie was working with a Patent Attorney at Clark & Elbing, who invited me to interview at the firm. Additionally, pursuing my own leads resulted in other interviews. In each case, the position for which I was interviewing was “Technology Specialist.” In the Boston area, and in other U.S. cities, law firms hire Ph.D. scientists who are interested in becoming Patent Attorneys, train them, and assist with the expenses of attending law school.

It was 1998 when I was transitioning from science to law. At that time, universities were not particularly supportive of their graduates pursuing “alternative careers.” There were no panel discussions of alternative careers, no events hosted by companies. Even joining a biotech company was frowned upon. But Connie and Cliff were always 100% supportive, as they were throughout my graduate tenure. Equally supportive were my new colleagues, who had made a similar transition from the bench and thus knew of the difficulties associated with the move.

What I do now as a partner is quite different from what I did as a Technology Specialist. In the early years, relied heavily upon my scientific knowledge. Having a broad knowledge base was important, as there were few patents relating to retinal development. My first projects at Clark & Elbing related to the production of transgenic fungus capable of efficiently producing antibiotics. Now, I rely more upon knowledge of the law than my knowledge of science, although the latter certainly remains important. The one aspect of my scientific training that has continuously served me well is the ability to critically analyze a collection of facts. The ability to do so is critical to the success of scientists and Patent Attorneys alike.

I am now the Hiring Partner at Clark & Elbing. It is my job to review resumes submitted by those pursuing a career in patent law. From my vantage point, it appears universities are more supportive of careers away from the bench. I am a frequent visitor to local universities as a participant in a discussion of career alternatives. What remains a challenge for the scientists is determining whether a career in law will be a fulfilling one. Certainly, I am exposed to science on a daily level. In some ways, the science is more fulfilling, as it is generally being applied to improving human health. The work environment is certainly different–suits and ties have replaced the shorts and sandals of my earlier days. How can a scientist considering a transition to patent law determine whether this career would be fulfilling? In short, there is no easy way. What was recommended to me, and what I recommend to others, is to talk with as many people as you can. Through these discussions, look to identify people who share your values. And feel free to write to me. As someone who made a similar transition (albeit quite a while ago), I’d be more than happy to help.

(9 votes)

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BSCB-BSDB Spring meeting
April 27 – 30, 2011
Canterbury University

Since I very much enjoyed last year’s joint conference of the British Societies for Developmental Biology (BSDB) and Cell Biology (BSCB) in Warwick, I was optimistic about attending the 2011 meeting in Canterbury. The organisers unknowingly scheduled it for the days around the royal wedding – apparently a royal wedding can be organised faster than a scientific conference; nevertheless it was rather well attended. This year’s programme differed drastically from 2010, with a number of more descriptive approaches, frequently involving live imaging and mathematical modelling. I will focus my meeting report on the part organised by the BSDB and will highlight talks which I found particularly interesting. I’ve grouped them in a way that seems logical to me, which does not necessarily correspond to their distribution into the meeting’s sessions. In this first part I’ll just summarise Mark Krasnow’s fascinating plenary lecture.

Mark Krasnow (Stanford University, USA) opened the conference by explaining the branching process of the mouse bronchial tree during lung development. His team found that despite the tree’s ultimate complexity, branching is highly stereotyped between individuals. With this knowledge, they reconstructed the sequence of branching events from hundreds of carefully staged fixed specimens, and thereby built an enormous lineage diagram of the ~5,000 branches of the bronchial tree. It turns out to be the result of merely three distinct geometrical modes of branching, which are deployed in three different sequences at characteristic times and positions in the developing lung.

Krasnow then went on to demonstrate the power of clonal analysis for identifying the origins of some of the dozens of different cell types developing simultaneously in the lung. They pinned down the progenitor niche for airway smooth muscle, which surprisingly is located at the budding – and therefore moving – tip of the airway branch. Moreover, they identified the plexus, a blood-containing net of tubular endothelial cells surrounding the airways as the progenitor cells for the lung’s pulmonary veins and arteries. Finally, they found that of the two types of alveolar cells (AT1 and AT2), AT2 cells can de-differentiate and serve as progenitors for AT1 cells. Even more intriguingly, this result has given them insight into the early events in adenocarcinoma, which is the major lethal form of lung cancer: Expression of oncogenic (activated) K-Ras in mouse AT2 cells leads to lung cancer, whereas this is very rarely the case upon random expression of activated K-Ras in the lung. This strongly suggests that AT2 alveolar cells might be the cell type of origin of lung cancers, contrary to common belief that bronchiolar cells are to be blamed.

The talk left me fascinated by the beauty of the developing lung and also astonished by how much there still is to be discovered in developmental biology – be it by simply tracking cells as organs develop, or by tracing the origins of cell types using methods that have been around for a long time, such as clonal analysis. The rest of the conference presented more examples of this kind, do come back here for more!

Metzger RJ, Klein OD, Martin GR, & Krasnow MA (2008). The branching programme of mouse lung development. Nature, 453 (7196), 745-50 PMID: 18463632

(7 votes)

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I was a PhD student with Peter Walter, studying protein translocation across the endoplasmic reticulum. I did very well as a student, publishing six research papers during that time. After that, I was a postdoc with Christiane Nüsslein-Volhard and then with Yuh-Nung Jan, studying oogenesis and pattern formation in Drosophila. Throughout my training, people handed me their papers to read and asked me to attend their practice qualifying exams because I was always looking for the big picture, always needing to know why they were doing the experiments in the first place. Time and again, friends suggested I become an editor. I mostly laughed at them, in part because I wasn’t really sure what an editor did, and in part because there seemed to be so few jobs for editors that I never thought I’d get one. Anyway, I was good at the bench and I couldn’t imagine disappointing my father by not taking a job in academia.

In 1993-4, I went on the job market, looking at standard faculty positions. I received some offers, including one from Vanderbilt University, where I am now. But I was resisting accepting a position, and some friends – who were also on the job market at the time – sent me to a career counselor. The counselor’s husband was a bench scientist, so she had some sense of my career until that point, and asked me a very simple question, one that I had never asked myself: “If you didn’t have to worry about how much money you made, or what anyone else thought of you, what would you do?” What surprised me was that I knew the answer to that question: I’d be a student for the rest of my life.

When I said that, I realized that what I loved about being in science was knowing something today that no one knew yesterday, and that it didn’t matter so much if I learned it by my own hands, or over coffee with a friend. This calmed me down a lot about the idea of starting up a lab, as I had been worrying about going around claiming other people’s work as my own.

When I got back to the lab that afternoon, I went into our lunch room and opened an issue of Cell. Near the front cover, there was an ad for an editor, and they were looking for someone with expertise either in cell biology (my graduate training) or developmental biology (my postdoctoral training) – and I thought to myself that it seemed an awful lot like being a student, so I applied for the position. The short version of this story is that I got the job, and I was a full time professional editor for about a dozen years, including a few very exciting years as the Executive Director of Public Library of Science, before returning to academia to my current position at Vanderbilt University. I still spend most of my time as an editor, most notably as the Editor-in-Chief of Development’s newest sister, Disease Models & Mechanisms.

Being an editor is really very much like being a student. You encounter lots of interesting and new science every day in a broad range of fields. But, at least for those of us who decide which research papers to publish in high profile journals such as Cell, it is also about being able to judge science. As an editor, you will have to turn away most of the papers you receive, and explain your reasoning. I think that editorial decisions need to be timely, constructive, transparent, and fair – or at least as much as they can be, given the need to turn complicated issues and shades of gray into stochastic decisions, and the need to keep confidential information confidential.

Editors and journals can be important partners to science. Through editorial policy they can help scientists do the right thing, such as sharing information and reagents; and through publishing policies, such as leaving copyright with the author or providing free access to published work, they can contribute to accelerating science itself. Editors are both gatekeepers and guardians of our treasury of scientific information, and editors need to behave responsibly and ethically. Thankfully, the Committee on Publication Ethics, of which Company of Biologists is a member, helps editors know and do the right thing.

For any trainees interested in being an editor at a journal like Cell, I encourage that you participate in journal clubs. A lot of the work of an editor is to assume the best of all possible worlds – that the conclusions are justified by the data and the interpretations are reasonable – and then assess how important the conclusions are to and beyond the field. Journal clubs are great ways to practice this – but be careful not to miss the forest for the trees, and to get too focused on the weakest part of the paper, which may be tangential to the overall conclusions. Also, take the time to go to seminars and meetings and talk to scientists in other fields and at other institutions. A scientist too buried in his own experiments to pay attention to the exciting discoveries around him is unlikely to enjoy or succeed at an editorial career.

Oh, and when I told my father, he was delighted. You see, he’d wanted me to be a writer, and considered this an enlightened combination of my twinned loves of science and language. And he was right.

(11 votes)

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The Node’s birthday is coming up on June 22nd and we’re currently preparing some things for that behind the scenes.

One thing that I’m working on are a few slideshows to present this summer at departments and conferences. In these presentations, I want to include some highlights from the Node’s first year, and I could use some help finding those. I could include my own favourites, but I’d rather hear what you liked, so tell me, please: what was the best thing you’ve seen on the Node all year? Favourite posts, favourite topics, favourite parts of the site, or any other comments are all welcome.

Have a look at the archives in the sidebar or the intro page for inspiration and reminders of what was on the site a few months ago. So many memories already…

Thanks for helping out!

(1 votes)

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To accompany our paper “Long-term live imaging provides new insight into stem cell regulation and germline-soma coordination in the Drosophila ovary” I have been asked by staff at the Node to discuss the path we took when developing a successful imaging protocol.

Germline follicle formation in the Drosophila ovary is a very dynamic process – involving the coordinated migration and division of many different cells and cell types. I was trying to study how two of these cell populations – somatic escort cells and germline stem cells together build germline cysts, the 1^st stage of follicle development. Whilst lineage data had suggested that germline cysts are generated by the coordinated division of one germline stem cell and two escort cells, actually finding examples of escort cells dividing in vivo was proving difficult, whereas dividing germline stem cells are found frequently. Escort cells are quite extraordinary cells; their nuclei are jammed in little cracks between large germ cells yet they have incredibly long, thin cytoplasmic processes that wrap the germ cells. These characteristics make escort cells pretty hard to see and therefore to study. I decided that the only way I was going to be able to make any progress in unraveling the escort cell/germline stem cell coordination mystery was to be able to watch both cell populations live in their native environment whilst they built a germline cyst. Given that cyst formation involves highly dynamic cellular behaviours and takes around 12 hours this was going to be quite a challenge.

Upon trying to image live germaria (the structure within the ovary that builds germline follicles) I immediately encountered a big problem – movement. The ovaries of Drosophila are subdivided into strings of developing follicles (called ovarioles) with the germaria at one end. Each of these ovariolar strings is surrounded by a sheath of muscle. Upon dissection the muscle contracts so that regular, peristaltic movements pass down the ovarioles causing them to flap around in the culture dish. The only method I found to prevent these contractions was to manually remove the muscle layer. Even then, I still had a movement problem; given that germaria are attached to strings of follicles some of which are an order of magnitude larger than a germarium, any little rocking or rolling movements of the large follicle would result in the attached germarium flying out of the field of view, and this appeared to happen frequently. I partially fixed this problem by dissecting flies that have just emerged from the pupal case, whose ovaries do not contain the more mature, larger follicles. Additionally, programming the microscope stage to move slowly and smoothly between each position during imaging helped. However, some movement remains despite trying many different methods to immobilize the tissue (including coating the dish with extra-cellular matrix components, draping the tissue with membranes and placing it in gels). Given that follicle formation is such a dynamic process, this is not entirely surprising. By re-focusing the microscope at regular intervals during imaging up to half of the germaria can be kept in focus for 12 hours.

Although overcoming tissue movement difficulties was a lengthy process, once achieved the path towards imaging success went quickly. This was thanks to the previous development by the Montell lab of culture medium designed to nurture more mature follicle stages that I found also supported follicle formation. Germaria could be cultured and imaged for greater than one entire cycle of follicle formation (14 hours). Once the method was developed and the first movies made the answer to the escort cell/germline stem cell coordination problem was almost immediately evident: Escort cells do not divide with gemline stem cells to generate a germline cyst which then migrates as one unit down the germarium, instead escort cells remain in one place, dividing rarely, and simply ‘hand-over’ the germ cells from one escort cell to the next. Demonstrating the ease with which dynamic processes can be studied when viewed unfolding in living tissue.

Morris, L., & Spradling, A. (2011). Long-term live imaging provides new insight into stem cell regulation and germline-soma coordination in the Drosophila ovary Development, 138 (11), 2207-2215 DOI: 10.1242/dev.065508

(5 votes)

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Genetic screens in flies brought me by chance to have a look at one of the basic apparatus of the cell: the actin cytoskeleton. At that time, I remembered my cell biology courses at University and since the actin cytoskeleton was not one of the hot spot, I though it was just a machinery required for basic cellular functions, from which, we knew almost everything. I quickly realized that in multicellular organisms, it was definitively worth to have a closer look at it.

Given the crucial role for F-actin in numerous cellular processes, it came to us as a surprise that triggering excess F-actin polymerization, by disrupting the activity of the actin-Capping Protein (CP) heterodimer, did not automatically lead to cell lethality, but could trigger tissue growth. We therefore focused our efforts on investigating how the control of F-actin could be involved in preventing cell proliferation. This gave rise to our recent story published in Development ” Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila”.

We quickly realized that many of the targets genes controlled by the Hippo (Hpo) tumor suppressor pathway were upregulated in cells lacking CP. This conserved signal transduction pathway, has emerged as a critical regulator of tissue size both in Drosophila and mammals. Central to the Hpo pathway is a kinase cascade, which involves the Hpo and Warts (Wts) kinases and their adaptor proteins Salvador (Sav) and Mats. Phosphorylation of Wts by Hpo prevents nuclear translocation of the transcriptional co-activator Yorkie (Yki) through phosphorylation, leading to transcriptional downregulation of target genes that positively regulate cell growth, survival and proliferation. Multiple upstream inputs are known to regulate the core Hpo kinase cassette at various levels. However, how they do so is poorly understood (http://dev.biologists.org/content/138/1/9.abstract). We observed that in cells lacking CP, upregulation of Yki target genes was associated to a decrease in phosphorylated Yki and its relocalization to the nucleus. These behaviours resulted from defects in F-actin since knocking down the Cyclase associated protein Capulet (Capt), which sequesters actin monomers, also caused abnormal F-actin accumulation and ectopic Yki activity.

At around this time, we were happy to hear that the laboratory of Georg Halder had also identified CP and Capt in a S2 cells genome-wide RNAi screen for genes that inhibit expression of a Yki-dependent luciferase reporter gene. Their story, just published in EMBO Journal (Sansores-Garcia et al.), shows a sticking correlation between the F-actin levels and Hpo signalling output. While knocking down actin modulators that prevent F-actin accumulation triggers Yki activity, depleting actin regulators that promote F-actin accumulation has the opposite effect. Their work nicely shows that this link is conserved in mammalian cells. They also confirmed that extra F-actin polymerization of cells knocked down for CP or overexpressing an activated version of the actin nucleator Diaphanous (DiaCA), causes tissue growth in vivo through Yki activity and not through disruption of apical-basal cell polarity or signalling in general. Interestingly, dsRNAi targeting the Cofilin twinstar (tsr) was also tested positive as a modifier of Yki activity in their assays. However, in Drosophila epithelia, we found that loss of tsr had no effect on Yki target genes. Although, epithelial and S2 cells require both a proper F-actin network to regulate Hpo signalling activity, the different effects of tsr loss on Hpo signalling output suggest that Hpo signalling activity uses different F-actin networks in tissues and in single cells. In epithelia, CP, Capt and DiaCA control F-actin formation near the apical surface, while Tsr acts around the entire cell cortex. Because the integrity of the apical domain of epithelial cells seems critical for the maintenance of Hpo signalling, in epithelia, but not in S2 cells, a specialized population of polarized F-actin,regulated by CP, Capt and DiaCA at the apical cell membrane, may promote Hpo signalling activity.

One interesting issue was then to determine at what level of the pathway, CP or F-actin dynamics in general intersect with Hpo signalling activity. We observed that overexpressing Hpo or the upstream regulator Expanded (Ex) suppressed growth of CP-depleted cells, suggesting a role for F-actin upstream or in parallel to Ex. However, overexpressed, Ex and possibly Hpo, also suppressed F-actin accumulation of Cpa-depleted cells. Moreover, we found that Hpo signalling activity prevented F-actin accumulation, independently of Yki activity. We were therefore confronted to the problem: what is first, the egg or the chicken. Nevertheless, our results indicated an interdependency between Hpo signalling activity and F-actin dynamics in which CP and Hpo pathway activities inhibit F-actin accumulation, and the reduction in F-actin in turn sustains Hpo pathway activity, preventing Yki nuclear translocation and upregulation of proliferation and survival genes.

In contrast, Sansores et al. observed that the DiaCA-induced overgrowth was not suppressed by Hpo or Ex overexpression, whereas Wts could do so. Thus, they conclude that DiaCA and therefore F-actin affect the Hpo pathway upstream of Wts but in parallel to Ex and Hpo. Interestingly, they also show that, unlike loss of CP, the accumulation of F-actin caused by DiaCA overexpression was not suppressed by Wts, Ex, or Hpo overexpression. The different effects of DiaCA and CP loss on Hpo signalling activity, when Ex and Hpo are overexpressed, argue that the control of F-actin by Hpo pathway activity is required to sustain its activity. By preventing F-actin accumulation of CP-depleted cells, increased Ex or Hpo may sustain Hpo pathway activity. In contrast, because overexpressed Ex or Hpo cannot prevent excess F-actin resulting from DiaCA overexpression, F-actin accumulation can still inhibits Hpo pathway activity. Alternatively, the different outcome of cells depleted of CP or overexpressing DiaCA, when Ex or Hpo are overexpressed, could result from different strengths of the CP loss of function and DiaCA phenotypes on growth. The effect of expressing DiaCA on growth were stronger than those caused by loss of CP, suggesting that Hpo signalling activity is only partially affected by the loss of CP. Overexpressed Ex or Hpo might therefore counteract the mild effect of CP loss on Hpo signalling activity but not the one of DiaCA overexpression. Finally, it is possible that F-actin acts at several levels to regulate Hpo signalling activity. Consistent with this possibility, F-actin has also been shown to control the activity of the MST1/2 Hpo orthologs in mouse fibroblasts. Moreover, we noticed that clones of cells mutant for CP affected Hpo pathway activity cell autonomously but also non-autonomously. Thus, the control of F-actin by CP activity may have a dual function in controlling Hpo signalling activity. Sansores et al. did not observe any non-autonomous effect on Hpo signalling activity in cells knocked down for CP using RNAi, suggesting that the non-autonomous disruption of Hpo signalling activity is less sensitive to F-actin accumulation.

All these data took us to bring one more piece to the complex puzzle of how Hpo pathway activity is regulated and convinced us, more than ever, that different populations of F-actin filaments exist in the cell that have specialized functions. The challenge will now be to identify these populations, understand how they are regulated and characterize their role in controlling specific cellular events.

Fernandez, B., Gaspar, P., Bras-Pereira, C., Jezowska, B., Rebelo, S., & Janody, F. (2011). Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila Development DOI: 10.1242/dev.063545

Sansores-Garcia, L., Bossuyt, W., Wada, K., Yonemura, S., Tao, C., Sasaki, H., & Halder, G. (2011). Modulating F-actin organization induces organ growth by affecting the Hippo pathway The EMBO Journal DOI: 10.1038/emboj.2011.157

(6 votes)

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Each year, the British Society for Developmental Biology awards the Beddington Medal for the best PhD thesis in developmental biology. At the 2011 BSDB meeting, this award went to Carlos Carmona-Fontaine, who completed his PhD in Roberto Mayor’s lab at UCL. Now a postdoc at Sloan-Kettering Institute in New York, Carlos returned to the UK to present his thesis work at the BSDB meeting. He gave a brilliant talk that included comparisons between insect migration and neural crest cell movement, as well as an auditory interpretation of the effect of chemo-attractants on harmonic collective cellular movement. Everyone in the audience (including Carlos’ parents!) enjoyed the talk immensely. I caught up with Carlos at the end of the conference to talk a bit more about locusts, music, and the trick to a successful PhD thesis.

Congratulations on the Beddington Medal. What was your thesis about?

Thank you. My thesis was about neural crest migration. Neural crest cells are a cell population in the embryo that can differentiate into different kinds of cells. But before differentiating, they have to migrate, and the way they do that is as a group of cells. This is called collective migration. What was interesting to me was that neural crest cells seem to be able to self-organise in order to get this coherent, co-ordinated movement, so I studied which kinds of cell-cell interaction allow for these coherent group movements.

Your Beddington talk yesterday covered a lot of ground. You were even talking about locust migration. What do locusts have to do with cells?

I had found a paper in Current Biology, by the group of Iain Couzin, about locust collective movement. I noticed that the kind of interactions they described were so similar to the interactions I was finding in neural crest cells, that I thought similar rules may apply, and we started collaborating.
Obviously locusts are very different to cells, but in mathematical terms the interactions between locusts or between migrating cells are very, very similar. If you look at attraction and repulsion, for example, “attraction” in insects could be a visual cue, whereas in cells it could be a chemo-attractant, but at the end of the day, mathematically speaking, they are the same thing: simple interactions that allow collective movement.

Besides locusts and cells, you also included some music in your talk. Can you explain what that was about?

One of the striking things of collective movement is not only that the cells remain together, but that they move in a coordinated way. I considered this to be harmonic movements, and was thinking of a way to represent that.
Then I heard a concert by Steve Reich. He’s a 21st century composer – one of my favourites. He has this piece called “Drumming”, which is only percussion. There’s a specific moment with a lot of xylophones and some drums, and they all seem to coordinate in this very random pattern. I was just amazed by this piece.
This gave me the idea of representing cell coordination in a similar way. It ended up as something a lot less musically pleasing than what Steve Reich does, but the idea came from there.

What are you doing now? Are you still working on neural crest cells?

No. I started a postdoc in New York about a month ago, and there I will eventually work on computer models of tumour growth. But the project is not entirely defined yet, and the idea is to explore a little bit at this point.

Do you have any advice for new PhD students?

Don’t stress, have fun – and pay attention to mathematical, and more quantitative means of biology. Even if you’re not an expert in mathematics, you can still try to get some inspiration from more physical and mathematical points of view. And have fun.

Read more:
Carmona-Fontaine, C., Matthews, H., Kuriyama, S., Moreno, M., Dunn, G., Parsons, M., Stern, C., & Mayor, R. (2008). Contact inhibition of locomotion in vivo controls neural crest directional migration Nature, 456 (7224), 957-961 DOI: 10.1038/nature07441

Bazazi, S., Buhl, J., Hale, J., Anstey, M., Sword, G., Simpson, S., & Couzin, I. (2008). Collective Motion and Cannibalism in Locust Migratory Bands Current Biology, 18 (10), 735-739 DOI: 10.1016/j.cub.2008.04.035

(11 votes)

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