-By Nitin Sabherwal, Eugen Nacu, Heike Laman, Irene Gutierrez Vallejo and Anna Kicheva

The second day of the workshop has finished and it is the reporting time now.

We had a wonderful day with fantastic talks and a nice walk around the area. The weather had also been beautifully supportive for these kinds of excursions and this added to the joy of walking around such a splendid place.

The first session on the second day had talks with the general question and theme- is it possible to control the cell fate decisions, particularly in context of neural development, by manipulating/controlling the cell cycle?

The session started with a talk by Philipp Kaldis who investigated the brain of CDK2/CDK4 double knock out (DKO) mice embryos. He found that the brain of these mice showed similar gross structures as the normal brain from control mice, however, the cortical plate and the intermediate zone areas showed reduced thickness indicating reduced differentiation, while the subventricular zone and the ventricular zone containing progenitors were largely unaffected. His work conveyed 2 important points:

1)   in the absence of CDK2 and CDK4, cyclinD will pair up with CDK1 and CDK6 instead.

2)   CDK2 and CDK4 have an effect on differentiation of neural stem cells. The effect is mediated by a change in the length of cell cycle and potentially by a direct effect of CDK2 and CDK4 on differentiation.

In the second talk, Federico Calegari, followed up on the theme of “cell cycle length (particularly the length of the G1 phase) being a determinant of cell fate during division of neural stem cells in the developing mouse brain”.  He started by describing the process of neurogenesis in mice, which follows thepath: apical progenitor -> basal (intermediate) progenitor -> neuron. He followed with explanation of previous work that supported this idea; work which showed that:

1) the G1 length of neural progenitors increases during development

2) cortical areas with higher neurogenesis have a longer G1 than proliferating progenitors

3) an artificial lengthening of G1 induces premature differentiation.

4) shortening of G1 by CDK4 and cyclinD1 inhibits neurogenesis and promotes the expansion of basal progenitors during embryonic development

And finally he showed the amazing results that it is possible to conditionally control the expansion of NSC in the adult mouse brain by temporarily overexpressing CDK4 and cyclinD1 (called 4D), which would initially expand the progenitor pool and then, after stopping the 4D overexpression by genetic manipulation, the expanded pool would eventually differentiate into the neurons. In essence, this new system allows the increase of neuron number in the adult hippocampus, which may have important implications for understanding the role of adult neurogenesis in cognitive function and controlling this process for therapy of neurodegenerative diseases

So we found out that controlling cell cycle length by CDKs and cyclins influences fate decisions in neural progenitors. But the next bigger question becomes- what is downstream of these Cyclin/Cdk molecules responsible for the fate change? And here came Anna Philpott’s insightful talk to our rescue.She looked at the posttranslational modifications of Neurogenin2 which drives neurogenesis. Neurogenin2 has multiple sites for phosphorylation and these different sites show different sensitivity to Cyc/CDK levels, with more sites being phosphorylated at a higher level of CDK. These phosphorylations were shown to negatively affect the stability of Neurogenin promoter binding in a cumulative fashion. Anna nicely showed that the efficiency of Neurogenin2 induction of neuronal markers is inversely proportional to the number of phosphorylated residues.

Linking the data together from Federico’s and Anna’s work, it is tempting to speculate that CDK4 and cyclinD1 induce proliferation of basal progenitors by decreasing the activity of Neurogenin2 and similar differentiation factors.

The last talk of the session was from Kristen Kroll who talked about the role of Geminin in setting up the epigenetic landscape for neural fate acquisition. Kris has long standing interests in how neural fate acquisitionis regulated by Geminin, which she cloned long time back in Mark Kirschner’s lab, as a regulator of both neurogenesis and cell cycle.  Kris nicely showed that knockdown of Geminin, a nuclear protein had no effect on the ability of ES cells to maintain or exit pluripotency, but when she overexpressed Geminin, it promoted neural fate acquisition, even in the presence of growth factors that normally antagonize neural induction. She followed this observation and showed that the mechanism behind Geminin’s ability for neural induction was due to its ability to maintain a hyperacetylated and open chromatin conformation at neural genes. She nicely showed that in ES cells, Geminin had the ability to enhance the histone acetylation on neural promoters and also it binds to the acetylated neural promoters and activate the expression of neural genes, leading to the neural fate acquisition caused by the Geminin overexpression. Thus Kris showed that Geminin functions as an intrinsic factor regulating the neural fate acquisition, by establishing an appropriate epigenetic signature on neural promoters.

During the Monday afternoon session we continued with two talks that link polarity and cell proliferation.  Dr. Helena Richardson presented her work in Drosophila eye imaginal discs about the role of lgl in proliferation.  lgl is a polarity protein that has been implicated in human cancers. Helena found that lgl mutant cells show an increase in proliferation without apparent defects in apical basal polarity. This proliferation mis-regulation is due to a perturbation of the Salvador/Warts/Hippo pathway, and she also presented her preliminary data on novel mechanisms that couple the polarity to the Hippo pathway.

Dr. Nancy Papalopulu spoke on her work on the early neural plate progenitor cells from Xenopus, In this system, cells with different apical-basal polarity properties showed different potentials for proliferation and differentiation. Her work shows that a membrane-bound, active form of aPKC, an apical polarity protein, is able to directly phosphorylate some components of the cell cycle regulatory machinery.  This caused protein destabilization with consequent effects on shortening the length of G1 phase, and promoting proliferation. She proposed that cell polarization is one mechanism that controls the length of the cell cycle, with consequent effects on the differentiation potential of the cells.

The fun (for scientists) continued in the evening with a mini grant writing session where five teams of randomly-paired discussants were asked to come up with a fundable proposal, that incorporated both team members expertise, in 15 minutes!! Proposals included microRNA regulation of oscillatory networks, proteomic screens on limb regeneration, uncovering links between patterning and proliferation, molecular requirements for NSC differentiation, and the importance of G2 phase.  Reflecting the current economic climate, none of the proposals was funded

(2 votes)

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Whether you’re familiar with the web comic or not, most of you will probably recognize your own current or past career as a graduate student in the new PHD Comics movie.

PHD Movie Trailer from PHD Comics on Vimeo.

It’s playing at university campuses across the world. If your city is not on the list, don’t fret: the website contains information on how to organise a screening at your own institute. Now if someone in Cambridge would like to host a screening, I’ll be there!

(See last year’s interview with Jorge Cham on the Node.)

(1 votes)

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Eric Wieschaus is a Professor at Princeton University, USA. He was awarded the Nobel Prize in Physiology or Medicine in 1995, together with Christiane Nüsslein-Volhard and the late Edward B. Lewis, for their work “uncovering the genetic control of embryonic development”. Throughout his career, he has been interested in the mechanisms underlying patterning and morphogenesis in the early Drosophila embryo. You can find a short film featuring Eric, made at The EMBO Meeting here.

 Marcos González-Gaitán‘s main interest lies in fly development as well. He started his lab at the MPI-CBG in Dresden, Germany, and in 2006, his group moved to the University of Geneva, Switzerland. Marcos has made major contributions to our understanding of how morphogen gradients are formed and regulate tissue growth. In his work, he combines cell biology and biophysics to address developmental problems in a quantitative manner.

I spoke to Eric and Marcos at The EMBO Meeting in Vienna last week. We talked about model systems, tackling details versus fundamentals, the future of developmental biology, and how to successfully collaborate with non-biologists. I hope you’ll enjoy reading about their experiences and thoughts!

What are currently the big scientific goals in your labs?

EW  I think I’ve always been interested in things that I can see. For me the focus is on morphological change – how cells change shape, how they move. I’m trying to do something slightly more biophysical, partially because I have this prejudice that physicists never have to remember much detail and you can get to an understanding without knowing all the details.

MG  What we are increasingly caring about is how tissues proliferate and grow, also taking a biophysical and cell biological approach. Of course I care about the details, but I try to see what can be fundamental beyond the details. I don’t know if it’s possible, because the details are contaminating the fundamentals to a large extent.

EW  Yes, and we’ve almost never done well when we don’t look at details.

MG  Exactly.

EW  I think this is actually a little frustrating about the time we’re living in, because overall in the field, we have this desire to go to a systems level, and yet at least for me how to do science is really grounded heavily in particulars. Describing something in a general, global way isn’t as helpful for me….

MG  I have very strong opinions about this, where I might be completely wrong in fact, but that’s how I think these days about this problem. We all speak about model systems, like Drosophila and I also work in fish, and with these you want to do something that can be general to other animals.

So, you start off thinking that the general description is at the level of genes. I don’t know what’s Eric’s opinion is on this, but over my career, I realised that that’s not really true – beyond saying that this gene is doing signalling, and this other one is a transcription factor. Beyond that it’s difficult to say that what Ubx does in Drosophila is the same as the homologous gene in another animal.

Then I became a cell biologist, because I thought these details might be general. I studied endosomes and endocytosis thinking that I’m going to find the principles of how endocytosis interfaces with signalling, and that’s going to be general. But, you also find out that that’s not the case, at least that’s my perception. The same endosome in the next system has totally different properties. It’s not general.

So then I moved into some biophysics and physics, thinking the universality is going to be in these physical properties, whatever they are – tension, mechanics or scaling of gradients. And now I’m getting to the point where this is probably also not true! Why is this? – I think its probably evolution; in every single system evolution has tinkered around with properties. So then where is our value?

My thinking today is that the real value is the approach. You ask questions to have solutions to these questions, and you develop tricks, assays – intelligent and elegant ways of thinking about the problem differently. In your little system, where the details are very important, you come up with a solution. I don’t think this solution is going to be universal. But the value, in my opinion, is that someone working in a different system can look at my study in flies or in fish and say, this is an interesting way of looking at the problem. You can measure degradation rates by doing FRAP, and then they can use these tricks or this way of thinking to apply to their system – the solution is probably going to be totally different.

EW  One thing that struck me was, you said that model systems are model systems because we think of them as leading to generalities. That is actually what the word means. The reality is that model systems, at least in the fields we work in, exist not because it has anything to do with generality, but because experiments were easy to do in them. We stupidly call them model systems, but we really work in them because I can go into the lab and have a chance of setting up an experiment in a way that leads to a conclusion that’s admittedly very specific. However, you’re not going to be able to do those experiments in anything other than the five or ten model organisms. So the real generality maybe is close to what you are saying, that the generality is that model systems allow the approach, allow us to pursue a scientific approach.

The curious thing, as biologists, we worry a little about generality, but one of the accusations the physicists make about biologists is that we don’t see the forest for the trees. We see trees all the time, it’s all we see, we see little specific trees. And my physicist friends worry a lot about whether what we’re doing is important, or generalisable? They always ask that question, and my reaction with time has become: Oh yes, it’s going to be generalisable, and somebody really smart some time down the road is going to see all of this, it’s all going to fit together in some picture – maybe! But right now I’m happy with trees, I’m happy that I can go into the lab and get something that is admittedly specific about flies, but at least is probably true, and measurable.

MG  The question is whether the problems we are addressing now, are comparable to trying to understand the double helix etc. We have the tendency to believe that it’s not, because we’re so much into our thing. But then, very often when people look back, they say, “These guys were doing absolutely fundamental research!”, but at the time they were just looking into this very particular thing. I ask this question all the time, are we looking at something fundamental or just the details. Because when I started to do developmental biology, I thought all my colleagues who did botany were completely boring, because they were just describing petals and sepals, while I was doing something fundamental. But with age, I’m not sure that I’m not just looking at petals and sepals, I’m not sure…

EW  Well you know, some day, somebody will know, but we will fortunately not be around!

In your view, what will be the future of developmental biology?

MG  I organise retreats in my lab, which often have this question – What is going to be the future in 5, 10 years. And it’s funny, my students and postdocs in the lab would say that the future is physics and to measure things. I think that’s not the future, that’s now! I have the feeling that we are neglecting some other things that might be the future, and that is chemistry. We think of proteins and genes, but there are all also lipids and sugars, and we are ignoring them completely! Maybe the future could be to measure them, find out where they are and how they influence things. Chemistry could be the future.

EW  Maybe the future is ignorance! Meaning where the future is, is where we’re ignorant today. So, in a way, asking where the future is, is to ask what are the things that we don’t know. That’s the question I never ask because if I would make a list of all the things I don’t know, I’d just spend all my time making that list. Beyond the idea that it’s just in the things we don’t know today, your job as a scientist is to find something you don’t know and figure it out.

MG  I think the future is determined by new ways of looking at things and then you can just ask different questions. For example, when I started my PhD with Garcia-Bellído, I was looking at work that he was proposing, and that Eric was proposing, which back then, meant to look at cells. At that time, developmental biology was not looking at cells at all – I’m talking 1985. So I thought the future is in cells, single cells, and it became the future in the 90s and 2000s. The same now with physics, people started to do this, so that can change the way we look at things and we will find things that we don’t know now. In this sense the new way of looking at it is maybe chemistry, but perhaps other things that my students may see one day, but not me.

EW  I suppose if you were an administrator at a university deciding where you’re going to throw money, clearly one of the places that you could decide to throw money is in re-vamping chemistry departments, which many places now do. And that might be another test of where the future is – it’s where the people who have money are throwing it!

So they might set the future by throwing money there, because money usually makes things possible?

EW  Yes, and when things become possible, unless people are cruelly incompetent, something good comes out of… going to the moon.

How did you start your collaborations with physicists, and do you have advice for others who are trying to do this?

EW  I’m totally dependent on proximity. I don’t like talking on the phone, I type badly, I don’t write – I have to have people who are next to me, and I have to get along personally with them. What helps me a lot is that I’m at a university that has a very strong commitment to undergraduate teaching. It’s a great university with a lot of very smart people, but we all teach undergraduates, and we all often teach together. And so a lot of my contacts with physicists or with computer scientists are through my teaching. It’s odd, because you think, “God if I didn’t have to do so much teaching I could be really, really good and accomplish all kinds of stuff!”, but for me, teaching has been a very important part of my scientific development over the past 30 years. It’s brought me into contact with colleagues and people that I wouldn’t necessarily have found common ground with.

MG  First, I think that very often biologists, when they go into these quantitative things have an agenda. They want to be proved right, and then they use these guys to prove them right. That is a short-term agenda. I think doesn’t work. In my case, I probably started in this way, but my main collaborator, Frank Jülicher, he’s a very deep person, and we have had to take our time to understand each other. Fortunately, we never had time pressure – we saw a problem and stepped back to the fundamentals. And we went slowly. It takes time; to me not rushing is something important. Second, I’m discovering that there is a component of personal chemistry and respect that is very important. The physicist needs to respect, appreciate and value, and want to understand the experiment and the details of it. And you need to do the same with their science; you need to understand how they solve the differential equations at some point because there is value in that.

What career advice do you give to your students and postdocs?

EW  Work hard! Really, work hard, and be successful. Meaning that make choices always based on “Is this going to be successful?”, and be able to make that judgement. Be able to change, be flexible. You have to work really hard; you have to work on the weekends and all these things. But it’s not an excuse after a year or two to say, “Well, I worked really hard, somebody should hire me.” They’re not going to hire you because you work really hard; they’re going to hire you because you’ve actually accomplished something. And it’s impossible to accomplish something unless you work hard, and you have to finish stuff. You have to bring things to conclusions.

MG  I’m more of a dreamer, I’m not so pragmatic. What I tell them is, value your career of course, but be beyond that, you want to understand something, and that is the uncompromisable thing. Do what is important to you, do work hard indeed, but go for a problem, understand something. I think that is the fuel to work hard and to improve your career. It allows you to relax a little bit about this pressure that everybody is feeling now, about crises, problems; you just focus on your problem. If you cannot do this, it does not work.

EW  Yes, it’s really hard to work hard if you’re not passionate. It is the passion I guess that allows you to believe that if you work hard, you’ll accomplish something.

(12 votes)

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Here are the highlights from the current issue of Development:

ApoE: a role in neurogenesis

Hippocampal neurodegeneration occurs in most forms of dementia, including Alzheimer’s disease. There is, therefore, intense interest in unravelling the mechanisms that underlie adult neurogenesis in this region of the brain. Now, on p. 4351, Steven Kernie and colleagues report that the cholesterol carrier apolipoprotein E (ApoE) is required for the maintenance of the neural stem/progenitor cell pool in the adult dentate gyrus region of the mouse hippocampus. The researchers show that ApoE is minimally expressed within the neural progenitor pool during early dentate gyrus development, when neural stem/progenitor cells are rapidly proliferating and differentiating into neurons. However, ApoE expression is markedly upregulated in adult dentate gyrus stem/progenitor cells, which proliferate more slowly. Notably, in ApoE-deficient mice, dentate gyrus neural stem/progenitor cells continue to proliferate rapidly, which ultimately depletes the neural stem cell pool. These and other data suggest that ApoE helps to regulate hippocampal progenitor cell fate and provide a mechanism by which human APOE polymorphisms might contribute to late-onset hippocampal neurodegenerative diseases.

A gutsy new model for intestinal development

The mechanisms that drive early intestinal development are poorly understood, but it is widely believed that the foetal intestinal epithelium is multilayered (stratified). Here (see p. 4423), Deborah Gumucio and co-workers overturn this dogma. By analysing cell polarity, cell shape and cell dynamics in the foetal mouse intestine, they show that the early intestinal epithelium is single-layered (pseudostratified) and undergoes interkinetic nuclear migration (a process seen in other pseudostratified epithelia, in which nuclei move from the basal to the apical surface of the epithelium during the cell cycle). They report that microtubule- and actinomyosin-dependent apicobasal elongation drives the growth of intestinal epithelium girth that occurs at mid-gestation and that villus formation occurs by expansion of the apical surface. Finally, they show that, as in the pseudostratified neural tube, the actin-binding protein Shroom3 is crucial for the maintenance of the foetal intestinal epithelium. These results suggest a new model for intestinal morphogenesis in which the epithelium remains single-layered and apicobasally polarised throughout early intestinal development.

Excretory systems: regeneration and evolution

Because planarians can regenerate a complete body from a tissue fragment they present a powerful system in which to study cell, tissue and organ regeneration, and to look for conserved developmental mechanisms. Peter Reddien and colleagues now describe a regulatory programme for the regeneration of the planarian Schmidtea mediterranea excretory system, the protonephridia (see p. 4387). The S. mediterranea protonephridia consists of tubules, which are dispersed throughout the animal’s body, two types of tubule-associated cells, and ciliated terminal cells, which drive filtration from the extracellular space into the tubule lumen. The researchers use RNAi screening assays and microarray analyses to show that Six1/2-2, POU2/3, hunchback, Eya, Sal1 and Osr, which encode transcriptional regulators, are involved in protonephridia regeneration. Notably, apart from hunchback, all these genes are also required for vertebrate kidney development. Moreover, the researchers show that planarian and vertebrate excretory cells express several homologous proteins involved in reabsorption and waste modification. Together, these findings suggest that metazoan excretory systems share a common evolutionary origin.

TPR-GoLoco moves to orientate division

Cell divisions must be correctly oriented, usually through mitotic spindle orientation, to ensure normal development. Extrinsic signals sometimes control division orientation, but how? To address this question, Adam Werts and co-workers have been investigating the localisation of the TPR-GoLoco protein pair GPR-1/2 in C. elegans embryos (see p. 4411). In four-cell stage embryos, GPR-1/2 is enriched at the junction between two cells – the endomesodermal precursor EMS and the germline precursor P₂ – and both cells align their division towards this cell-cell contact. The researchers report that, unexpectedly, GPR-1/2 distribution is asymmetric in P₂ but not in EMS. Instructive intercellular signalling through MES-1/SRC-1 determines the asymmetric localisation of GPR-1/2 in P₂, they report, and this distribution (which is established through GPR-1/2 destabilisation at one cell contact, and its diffusion and stabilisation at another cell contact) is important for normal development. Overall, these results identify the dynamic localisation of GPR-1/2 as a key mediator of cell division orientation in response to external signalling.

Mediator complex sizes up plant development

Final organ size is regulated by coordinated cell proliferation and cell expansion, which control cell number and cell size, respectively. Little is known about how organ size is determined in plants, but now, on p. 4545, Ran Xu and Yunhai Li report that MEDIATOR COMPLEX SUBUNIT 25 (MED25) regulates organ size in Arabidopsis thaliana. The researchers discover this new role for MED25 – a gene that controls shade avoidance and stress responses in Arabidopsis and is involved in transcriptional regulation – through a genetic screen for mutations that enhance the floral size of the da1-1 mutant; DA1 is a negative regulator of seed and organ size that restricts cell proliferation. Loss-of-function mutants in MED25 form large organs, they report, whereas plants overexpressing MED25 have small organs. These alterations in organ size are caused by changes in both cell number and cell size. Thus, the researchers suggest, MED25 acts within the transcriptional machinery to regulate plant organ size by restricting both cell proliferation and cell expansion.

Axons set oligodendrocyte myelinating potential

Myelination facilitates the transmission of electrical signals along axons and ensures their long-term viability, and most axons in the central nervous system are eventually myelinated by oligodendrocytes. But are the timing and extent of myelination regulated by the intrinsic properties of oligodendrocytes or by axons? To address this question, David Lyons and colleagues examine myelination by single oligodendrocytes in vivo in zebrafish (see p. 4443). As in mammals, zebrafish oligodendrocytes myelinate either a few large caliber axons or numerous smaller axons, they report. They further show that the large caliber Mauthner axon is the first axon to be myelinated. Then, using two independent genetic manipulations, the researchers generate zebrafish that have additional Mauthner axons. In these fish, oligodendrocytes that typically myelinate one Mauthner axon in wild-type fish myelinate multiple Mauthner axons, and oligodendrocytes that exclusively myelinate smaller caliber axons in wild-type fish also myelinate the supernumerary Mauthner axons. Thus, the researchers conclude, individual axons regulate the myelinating potential of single oligodendrocytes.

Plus…

The Wnt signaling pathway controls lineage specification and axial patterning in vertebrate embryos and, as reviewed here by Sergei Sokol, recent studies have uncovered a new mode of Wnt signaling that acts to maintain pluripotency in embryonic stem cells.
See the Review article on p. 4341

The International Workshop on Molecular Mechanisms Controlling Flower Development took place in Italy in June 2011. As reviewed by Francois Parcy and Jan Lohmann, the results presented at this workshop underlined how mechanistic studies of both model and diverse species are deepening our understanding of the cellular processes involved in flowering.
See the Meeting Review on p. 4335

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We are looking for a highly motivated PhD student to study development and regeneration of the thalamus in zebrafish.

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke. In 10% of all stroke patients, a remote damage of the thalamus has been documented.

We utilize the genetic model organism zebrafish to explore innovative strategies for the improvement of regeneration by means of tissue engineering. The main focus is on the analysis of the development of the zebrafish thalamus and on the design, and testing of an 3D-cell culture system for reconstructing this complex brain part in-vitro. In order to optimize the strategy for tissue engineering, the project is aimed at reaching a new level of innovation which brings together (in a transdisciplinary approach) the main pillars of tissue engineering, namely 1) Developmental biology, 2) Microsurgery and Transplantation of tissues and cells, and 3) Material science. The project is set in a collaboration Dr Stefan Giselbrecht (IBG1, KIT; http://www.ibg.kit.edu/ibg1/57.php ).

The ability to quickly integrate into a team and to work within an academic research environment is essential. You must show initiative, should be well organized and must pay attention to detail. General laboratory management skills are required. You should have a very good degree in a subject related to molecular biology or cell culture. Previous experience with zebrafish would be an advantage.

The position is implemented in the Graduate School of the Biointerfaces Program of the KIT   ( www.bif-igs.kit.edu ) and is available for 3 years. The project could start any time.

For further information and/or application with CV and a short statement of your current research please contact:

Dr. Steffen Scholpp

Karlsruhe Institut of Technology (KIT); Institute of Toxicology and Genetics (ITG); Email: steffen.scholpp[at]kit.edu; WWW: http://www.itg.kit.edu/scholpp.php

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Okinawa institute of Science and technology (OIST), situated on Okinawa Island is an ideal and inspiring place to discuss and learn science. The student participants and mentors of the developmental neurobiology course (July 17- 31, 2011) were from every corner of the globe. The course began with a wonderful talk about history of developmental neuroscience by David Van Vactor. M.A Price spoke about the signaling mechanisms during early development of Drosophila embryo.  James Briscoe from MRC London discussed about brain and neural tube development in vertebrates. Explained, “How does neurogenesis begin and how do neural stem cells maintain their fate”.  Chris Q. Doe from Oregon USA very elegantly described the mechanisms involved. Prof. Ischiro Masai from OIST Japan explained factors involved in spatial and temporal pattern of neurogenesis in Zebra fish retina. Kozo Kaibuchi from Nagoya University, Japan presented how internal and external signals regulate neuronal polarity. How do axon find their right partners and make neural connections, were the major focus of Elke Stien, Hitashi Sakano and J Huang. Students very enthusiastically and actively discussed their work too during the poster sessions in between.  After two days of intense lab work at the main campus, participants could also visit the labs of various groups. Personally talk to researchers and use the lab facilities for experimental work. Drosophila and Zebra fish were mainly used during the practical sessions in the course.  Students learned dye injection into embryonic Zebra fish eye to visualize the connections in wild type animals and then compare with the mutant animals. They got opportunity to do live imaging using Zebra fish and Drosophila embryos. Dissection of embryonic and larval Drosophila nervous system was also performed during the session. Participants could visualize and experience good microscopy by trying out their samples on microscopes from the Institute imaging facility. We also utilized and tried out different kinds of microscopes, which were provided by various companies in the workshop. Image analysis soft wares were also used for data analysis.

Second week of the course started with session on axon targeting and synapse specificity. Akiko Nose from Tokyo University taught how the connections are made and then refined to form a proper functional synapse. He showed some nice movies using optogenetics as a tool. The molecular mechanisms for dendritic self-avoidance and tiling, how is dendritic field size regulated and how are these maintained over time were the major themes of the Prof. Yuh Nung Jan’s talk. He also explained how fruit fly maggots avoid sunlight and described in detail how class IV dendritic arborisation neurons with elaborate dendrites tiling the entire body wall, act as light-sensing antennae. Van Vactor from Harvard school of Medicine shed light on the posttranscriptional machinery of growth cone involved in regulation of synapse assembly. He also discussed his recent findings from the lab about modelling spinal muscular atrophy, a severe neurogenic disease in Drosophila. Vijay from NCBS India explained, how the behaviour output is generated, once the neural circuits are established. He illustrated various assays to quantify behaviour deficits in mutant animals. At the end of the session Hitoshi Okamoto from RIKEN brain Institute described how Zebra fish could be used as a model to study vertebrate behaviour. He explained various behaviour assays to study learning and memory in Zebra fish. We relaxed and also got chance to show our non-scientific talents in the party and dinner at faculty house located nearby the seaside house. We also visited Castle and Aquarium during the course. After fun and enjoyment we attend talk by David Feldhiem, who described how graded expression of Ephrins is involved in generation of topography in vertebrate visual system. Bernando sabatini discussed about various high resolution imaging techniques utilised to study active synaptic connections. In the last of course Takeharu Nagai described broad range of fluorescent probes to image the synaptic structures and how to choose a good fluorescent probe for your experiments. Prof Hideyuki Okano discussed about iPSCs and their use in treating various neurological disorders and injury. Prof. Lee Rubin at the end of the course demonstrated how we could do large-scale drug screening in the lab in collaboration with pharmaceutical companies to treat challenging nervous system disorders. Last but not least, at the end of the last supper, we enjoyed the traditional Japanese dance and Judo Karate. In short this course was full of fun and learning.

You can read more about OIST and Course here

http://www.oist.jp/en/press-room/news-articles/151/1062-dnc2011.html

and watch this video also.

(8 votes)

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In the series of The Company of Biologists Workshops a select group of roughly 30 scientists have gathered at Wiston House, West Sussex, UK, from September 18 to 21, 2011, to discuss the topic of “Growth, division and differentiation: Understanding Developmental Control”. This workshop series aims at fostering collaboration and conceptual advancement by bringing together researchers from various backgrounds and by facilitating close scientific exchange and cross-pollination to tackle challenges in current biological research.

We are a group of workshop participants – PhD students, postdocs and lab heads – who will be updating the Node with collectively written posts from the meeting. All speakers have approved the text before it was posted.

The scientific program of the opening afternoon session on Sept. 18 included a series of four excellent plenary talks followed by an evening poster session.

Ludger Hengst from Innsbruck Medical University (Austria) opened up with a talk elucidating the role of the CDK inhibitor p27, specifically its regulation by growth factor-related signaling molecules such as JAK2, exemplifying how tyrosine kinase signals can directly modulate cell cycle regulators and underlining the immediate clinical relevance, for example, in the context of JAK2 mutations in proliferative diseases such as polycythemia vera.

Jackie Lees from MIT presented work on the role of the Rb tumor suppressor in fate commitment and cancer. To elucidate tissue tropism and heterogeneity of Rb-associated tumors (here: osteosarcoma) this work exploited Rb-/-, p53-/- as well as Rb/p53 double mutants in Osterix-positive bone precursor cells [see Calo et al., 2010]. In an E2F-independent mechanism, Rb appears to potentiate Runx2 serving as an activator in osteogenesis. While Rb mutants did show surprisingly little effect, the combined Rb/p53 deletions not only lead to blockage of differentiation at the pre-osteoblast stage, but to a reversion toward even earlier stages, enabling this earlier stage mesenchymal precursor to give rise to an extended spectrum of derivatives including brown fat tissue tumors (hibernoma). Re-introduction of Rb reinstated terminal bone differentiation. This work also illustrated how the heterogeneity of tumors could arise from the dedifferentiation of more mature stages, so that tumors may contain cells with stem cell character without necessarily having arisen from a “cancer stem cell”.

While Ludger Hengst’s earlier presentation had primarily drawn attention to N-terminal interaction partners of p27 during late G1, the next talk by P. Renee Yew from the University of Texas focused on its C-terminal regulatory interaction. To this end, the work presented here introduced the Xenopus inhibitor of CDKs Xic1 (exhibiting both p21 and p27 features) and showed novel regulatory interactions with PCNA during S-phase of the cell cycle.

Peter Sicinski, Harvard Medical School, presented data on a cell cycle regulation-independent role of Cyclin-E on CDK5 in the generation and functionality of neuronal synapses and demonstrated its relevance for cognitive behavior in mouse models. In this context, CDK5 appears to partner with p35 and p39 to execute its essential function in neuronal differentiation and synaptogenesis. On the other hand, formation of a cytosolic complex with Cyclin-E and p27 appears to render it inactive and profoundly interferes with synapse formation and learning.

This concluded the first day’s session of oral presentations. A common thread were the identification of novel linkages between classic cell cycle machinery and a range of signaling pathways involved in the control of differentiation. So inspired, ample discussion continued throughout the evening poster session and beyond.

(5 votes)

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Scheduled Node Maintenance:

This weekend (September 16-18) we’re upgrading the system that the Node runs on (WordPress), so you may not be able to access the site at times. Everything should be working again on Monday, but as always, if you spot anything unusual, let us know.

Update 18/9: the site upgrade is now complete, and everything works – as far as we can tell (again, do let us know if something seems weird.)

Dates for your calendar
In the recent survey about the Node, a few people asked to be kept up to date of various scholarships and registration deadlines. Here is a selection of upcoming dates of interest, but this is by no means an exhaustive list. We’ll try to do these once in a while, but don’t hesitate to write your own posts to let people know about similar deadlines, or leave a comment below. Also make sure to check the eligibility of all scholarships and grants before applying.

Conference registration deadlines.
Keystone announced a few upcoming deadlines for conference abstract submissions, including dates for the following meetings:
September 19 – abstract & scholarship deadline for “Angiogenesis: Advances in Basic Science and Therapeutic Applications” (January 16-21, 2012)
September 20 – abstract & scholarship deadline for “Epigenomics” joint with “Chromatin Dynamics” (January 17-22, 2012)
September 21 – abstract & scholarship deadline for “Cardiovascular Development and Regeneration” (January 22-27, 2012)
October 6 – abstract & scholarship deadline for “Gene silencing by small RNAs” (February 7-12, 2012)

Grants and fellowships:
October 11 – The NSF announced an application deadline of October 11 for Postdoctoral Research Fellowships in Biology (PRFB). For 2012 this fellowship is limited to certain areas: (1) Broadening Participation in Biology; (2) Intersections of Biology and Mathematical and Physical Sciences; and (3) National Plant Genome Initiative Postdoctoral Research Fellowships.
November 1 – Sir Henry Wellcome PostDoctoral Fellowships. See their website for other grant deadlines.
November 18 – NSF Graduate Research Fellowship Program (GRFP)

Travel funding:
September 30 – Deadline for The Company of Biologists Direct Travel grants, which fund travel for conference attendance.
October 31 – EDEN has research exchange funds available for US-based eco-evo-devo researchers (graduate students, postdocs, faculty).

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The famous Richard Axel kicked off the last day in Vienna by presenting new data on how olfactory information is projected from the olfactory bulb to the cortex. After his keynote lecture, the talks in the plenary session continued with a focus on the brain and how it drives behaviour in different circumstances or environments and in different organisms – we watched flies, mice, fish and worms as they (mis)behaved. Especially David Anderson‘s movies of aggressive flies and mice had a certain entertainment value!

In the afternoon I found it hard to make a decision which of the five concurrent sessions to go to. I would have liked to attend the RNA session, Asymmetric Cell Division and Quantitative Principles of Morphogenesis, all at the same time! Since I had interviewed Eric Wieschaus and Marcos González-Gaitán at lunchtime, I picked their session on morphogenesis. I’ll be posting their insightful discussion here on The Node soon.

The session turned out to be a very good choice, full of fascinating movies of developing embryos. Eric Wieschaus talked about the mechanisms Drosophila embryos deploy to form two different kinds of folds during gastrulation: transient epithelial folds versus permanent internalisation, the latter ultimately leading to the epithelial-mesenchymal transition. How planar cell polarity is re-oriented during development of the fly wing was the focus of Frank Jülicher‘s talk, and Marcos González-Gaitán presented their impressive quantitative analysis and modelling of how growth is regulated by the DPP gradient in the developing fly wing. Benny Shilo continued the fly theme with their analysis of the mechanism that establishes the sharp Dorsal gradient in the early embryo.

The two final speakers represented the growing number of vertebrate researchers addressing questions of morphogenesis in a quantitative manner. Martin Behrndt, a PhD student in Carl-Philipp Heisenberg‘s lab, talked about the process of the squamous epithelium spreading over the yolk cell during zebrafish gastrulation, and how they took a biophysical and modelling approach to decipher this mechanism. Alexander Aulehla ended the session by presenting a quantitative live-imaging system to tackle the question of the oscillations of gene expression during somitogenesis in mouse.

All in all, I found the meeting very enjoyable. The evening events made it easy to socialise and network, and the scientific programme was at a very high level. The size of the meeting sometimes made it hard to pick one of the parallel sessions, but I think that’s a good problem, when there are simply too many interesting talks on offer! I’ll definitely try to be there in Nice in 2012.

(6 votes)

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I arranged to talk to Professor Janet Rossant after her talk at The EMBO Meeting here in Vienna. Janet is Chief of Research at The Hospital for Sick Children in Toronto, besides being a University Professor at the University of Toronto. Throughout her career she has been and still is making major contributions to the understanding of early development of the mouse embryo.

During the interview I took the opportunity to ask her about her career, her thoughts on the future of developmental biology and for some advice for young scientists. I hope you enjoy reading it as much as I did talking to Janet!

Why did you become a developmental biologist?

When I was an undergraduate many years ago in Oxford, I was taught by John Gurdon. John Gurdon is one of the world’s famous developmental biologists, still active and he did all the early work on Xenopus embryos, nuclear transfer embryos. He really got me excited about this idea of how it is that a single cell develops into a whole organism, and how you can begin to manipulate embryos, understand particularly the early stages. So I found that really exciting.

After I finished my undergraduate degree I thought I’d do research. So I talked to John, who suggested that I might talk to Chris Graham, who had started to do the same things in mouse embryos. Chris sent me to Richard Gardner, who was starting to make mouse chimeras, and I switched into mouse. I’m still interested in the fundamental question how the embryo develops, using the mouse system. And I must say that in the time – I switched to the mouse system in the late 70s, because I thought the Xenopus system was passé! Well, I was right about the mouse being an important system, but I was wrong about Xenopus, I apologise. I’ve stuck with the mouse ever since. Occasionally we’ve played a little with fish and various other organisms, and now of course we’re doing some stuff with human embryonic stem cells. Really that’s a direction we’re moving into, taking mouse development and trying to understand human development.

You’ve been involved in the public debate on the ethics of stem cell research and studying human development in Canada. What role did you have there and did you enjoy doing it?

Well, yes and no. There have been some very educational parts of that. As the human stem cell debate started to rage it became very clear to me that as developmental biologists and stem cell biologists we had to get involved. You can’t sit back and let the right wing politicians and lobby groups try to succeed.

I got involved through the CIHR, the funding agency for health research. They set up a panel to look at guidelines for human embryonic stem cell research, and I chaired that. So that would have been my first entree. With that we also had to appear before parliament and parliamentary committees. I’ve done quite a lot of public lectures in this area, to try to put forward the science, without necessarily getting into the ethical debate. At the end of the day, when people believe that a human embryo from the time of conception is worthy of all protection, you cannot argue against that. All I can argue is that we are in a situation where human embryos through IVF programmes are discarded, and isn’t it more ethically acceptable to use those discarded embryos to help save human lives in the future? I think that’s, the overall societal consensus pretty well worldwide and most people actually believe that that’s a doable thing.

You do have to educate people, and of course there are extreme groups who will not change their mind, but society can’t respond to extreme groups. Society as a whole has to come up with a consensus and we need public debate, and we need forums in which to do that. So I think it’s very important for scientists to get involved. Nowadays the CIHR guidelines exist, we have a regulatory environment, and human embryonic stem cell research is certainly proceeding in Canada. We also can undertake some forms of human embryo research, again with all the right conditions and approvals, unlike the States, where with federal funding you can work with existing cells, but you cannot use embryos or make new cells. In Canada we can, if approved, so it is a big advantage.

You’re British, but you ended up in Canada. Why, and have you ever considered coming back?

It’s simple, I married a Canadian. But it’s turned out to be very good; I’m still married to him, and I really enjoy having a career in Canada, it’s been great. I certainly looked occasionally and I obviously have a lot of colleagues and family still in the UK, associations I’d like to keep up. I don’t think at this stage I’m likely to move back in any major scientific role, but never say never, we’ll see!

What were the most exciting moments during your career?

First of all, we were very early involved in doing knockout mice. Oliver Smithies and Mario Capecchi had just shown that homologous recombination was possible in ES cells. My colleague Alex Joyner and myself knew that if we wanted to study genetics in the mouse, we needed to be able to knock out genes. So we got really excited, and she and I together worked on making our first knock out. Getting the first PCR to see that we had actually knocked out the gene was very exciting. It was Engrailed-2, a homeobox gene that Alex had worked on. In retrospect, we were lucky because the frequency we got was quite high – Alex had a postdoc working for months after that to knock out Engrailed-1, who could not do that at all! It turned out to be because there were some genetic variations between the clones, so eventually it worked. So we were very lucky. At the time it was so exciting, you could give a seminar and say you’ve managed to make a knock out and they’d be falling out the door and try to find out how you did it.

The other one was whole-mount in situ hybridisation in embryos. Today everyone knows all the beautiful pictures, we can do movies, we can do everything. But being able to actually see patterns of gene expression in embryos, as opposed to even sectioned materials, where it’s hard to reconstruct the complexity of the embryo, was fascinating. People had done whole-mount in situs in Drosophila, but in the mammalian system, we were having a lot of trouble. One of my postdocs worked very hard to get whole-mount in situs working in the mouse embryo – everybody does it with Brachyury first because it’s so easy to see, but we cranked it up to see other genes.

I remember Siew-Lan Ang, who was working at the time on looking for novel orthologues of Drosophila genes. She cloned Otx2, an orthologue of Orthodenticle, involved in anterior function in the fly. She took me to the microscope one day, and said, “What do you think of that?” I looked down the microscope and there was a late gastrula, early neural fold embryo in the mouse where you can’t really see anything, it all looks the same and there it was, front to end Otx2 positive, a strict boundary, nothing behind, amazing. Those kinds of things, they really grab you.

What advice do you give to your students and postdocs today?

First of all, you have to follow your passion, because at the end of the day you have to be grabbed by a question and by your research if you really want to drive it through. If the passion isn’t there, then you’re probably not in the right game.

Secondly, I think today life is complicated, and there are so many opportunities. So I really encourage people to think about the different kinds of tools that one can apply to a question. Try to combine, as we’ve heard it in these talks today, precision of looking at a question, or a stage, or a process with some of the tools of systems biology to try to get out an integrated model. I think that to me is the biggest challenge, whether it’s in the embryo, in stem cells or anywhere else. You don’t even always have to do the data yourself, there’s a lot of in silico data out there that you can capture.

Where do you think developmental biology as a field is heading?

It’s a mature field, interestingly. You see that at meetings. We certainly don’t have all the details, but we do have a good fundamental understanding of how to put a fly embryo together, a mouse embryo, a frog embryo. We do know the main players, and when I look back, we didn’t! Hox genes were cloned; nobody knew they were going to be conserved across evolution, and nobody believed they were really doing the same things if they were conserved. It’s hard to put your brain back at that time. Conservation of function across development has opened up our ability to look at the systems, and the similarities and the differences have really been worked out.

So I think that we are getting into the details of developmental pathways. It’s going to go in the systems approach, it’s going to go down into the cell biology – how cells are behaving in embryos. The area we’ve been trying to move into is to use it perhaps more directly in a translational sense. To me, the exciting things around embryonic stem cells and iPS cells is trying to combine developmental biology to drive embryonic stem cells to look at human development and model disease. And I really start to think can we use that for new drugs and new therapies.

So, developmental biology, as ever, sits in a very interesting convergence area, where you can move into many different directions. My personal direction is two-fold: Get into the details of that blastocyst, and the other is to move towards human development and disease.

But developmental biology still is fundamentally interesting. The other thing that people do, and I don’t really recommend my people to do it, is of course Evo-Devo – it’s fascinating, but it cannot easily get funded. Unless you’re a Howard Hughes investigator, it’s very hard. If that’s what people care about and want to do, that’s fine. I think it’s very important and exciting, but in the broadest sense it’s hard if you want to get forward, since it’s hard to get funded.

What were the biggest challenges you had to face during your career, and how did you deal with them?

When I started in Canada in 1977, there were not many jobs anywhere at the time, since a lot of the universities in the UK, US and in Canada had done a big expansion in the 1960s, so all those professors were sitting in their positions. I ended up at a small university, Brock University, teaching biology and doing research. So the biggest challenge I had was to go from Oxford and Cambridge to a small university in a country I didn’t know, trying to make contacts and all the rest of it.

The way I took on that challenge was to stick at it and to network, network, network! So I went out from Brock and I found people to collaborate with. I did a lot of collaborations with Verne Chapman in Buffalo and I collaborated with people in Toronto, so that’s how I ended up in Toronto. You can’t sit and feel sorry for yourself, you have to go out and do something about it. In those days I had to actually get in the car and drive around, these days you’d probably skype with people all over the world and stay in your lab. But actually, I think it can’t work exclusively that way, you still need that personal contact.

If you weren’t a scientist, what would you like to do?

I don’t ask myself that so much anymore, because I’m getting to the end of my career. So if I’d lost all my grants now I could just stop doing anything. But in the middle of your career, when things are looking rough, you ask yourself, “What would I do?” – I honestly don’t know. I certainly enjoyed teaching when I was at Brock; this is again a piece of advice to researchers, do some teaching! It’s awfully good practice for learning how to give talks and communication, because it’s all about communication.

However, I did get a bit tired of teaching first-year biology and sit on the exams and all that. So I’m not sure I’d have the patience to do that forever. I like to cook, but starting a restaurant – forget that! Maybe I could have a small catering company. I also do quite a lot of administration, since I run a big research institute, so I always got involved in science policy and science administration. So I guess fallback, that’s what I would end up doing. But at the end of the day, although I actually enjoy that, I can’t leave the research behind, it has to be part of the equation.

What would we be surprised to know about you?

That I like watching Top Gear!

(13 votes)

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