As a follow up to Ben Martynoga’s post from yesterday, here is some more information on the topics covered in this excellent workshop that took place a couple of weeks ago.

After extensive revolutions around the cell cycle in many of the previous sessions, Ryoichiro Kageyama introduced quite a different rhythm to the meeting in the afternoon session where he talked about Hes1 oscillations in embryonic and adult neural stem cells. Ryoichiro showed impressive live-imaging data from reporter constructs that allow his lab to visualize these oscillations. Besides being an exciting thing to watch, these oscillations are also important to balance self-renewal and neurogenesis during development, as Ryoichiro showed.

The next talk of the session by Nick Monk then took quite a theoretical approach to the same topic. Instead of Western blots and fluorescent micrographs he showed a lot of colorful simulations, which he used to investigate how in theory the oscillators described by Ryoichiro can be built by connecting the different components of the Delta/Notch signaling system. Nick showed that communication between single cells can make a big difference to the oscillatory dynamics. Communication therefore is essential not only for scientists, but also for their study objects.
Marc Kirschner from Harvard Medical School then gave the plenary talk of the meeting. He presented a balance with which to weigh single cells, and described how it can be used to address a very fundamental question in cell cycle research: How are cellular growth and cell cycle integrated to control size variability in cell populations? His talk perfectly set the tone for the evening session, where the participants together aimed at identifying the future big questions in the field. What became clear is that we’ll probably move away from searching for more and more kinases and phosphorylation sites, but will rather focus on integrative approaches. We may for example aim at understanding how the modules that drive cell cycle and growth are integrated and exchange information, how cells generate, sense and react to tissue level signals, and how the characteristics of the cell cycle differ in development, tissue homeostasis and disease.

(2 votes)

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October 7 is Ada Lovelace Day, celebrating women in science and technology. This international day to promote gender equality in these fields was first held in 2009, and is named after Ada Lovelace. Ada Lovelace is considered to be the world’s first computer programmer – although in the 19th century, they weren’t called “computers” yet! Ada wrote algorithms for Charles Babbage’s “Analytical Engine“.

A few related resources to mark the day:
-The Journal of Cell Science‘s “Women in Cell Science” interview series by Fiona Watt.
-“Mothers in Science: 64 ways to have it all“, a free eBook published by the Royal Society and produced by Ottoline Leyser (who has a bit more to say on the topic in an upcoming interview with Development, so watch this space in a few weeks.)

Who inspired you?
In many areas of science, women are underrepresented at all levels. In other fields, such as chemistry or molecular biology, the distribution is still quite even among students, and then drops dramatically among more senior scientists. Developmental biology, on the other hand, seems to suffer less from a lack of women than many other areas of science. In 2010, more than half of the presidents of national developmental biology societies were women! In addition, quite a few women have made significant seminal contributions to developmental biology over the years and are role models to many: Nicole Le Douarin, Christiane Nüsslein-Volhard, or Anne McLaren (see also here), to name just a few of them – but there are many others!

The organisers of Ada Lovelace Day are asking people to “share your story about a woman — whether an engineer, a scientist, a technologist or mathematician — who has inspired you to become who you are today.”   So who is your female role model?

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Better late than never! This excellent workshop took place a couple of weeks ago, but it is still nice to have a record of what was discussed, here on The Node.

Fabienne Pituello started the day by describing how the Shh pathway can induce cell cycle regulators such as Cdc25b to increase the rate of neurogenesis in the developing ventral spinal cord of the chick. In keeping with other talks throughout the meeting her data supports the idea that modulating the length of specific cell cycle phases can affect the outcome of progenitor division. Working in a completely different model, the Xenopus retina, Muriel Perron explained how Hedgehog signaling has a highly analogous function in promoting rapid, neurogenic divisions in her cellular system of choice. She went on to show that this pro-differentiation activity of Hedgehog is counteracted by Wnt signaling, which instead promotes stem/progenitor cell maintenance. Furthermore Wnt and Hh seem to mutually antagonize one another, probably via the induction of direct target genes that modulate the other pathway.

Bill Harris, who also studies the development of the retina, gave a very convincing illustration of just how powerful live imaging in vivo can be understand the real dynamics of cell cycle progression and cell fate choices. For example, a simple genetic reporter where PCNA is fused to GFP can be imaged to quantify how long individual retinal progenitors spend in each phase of the cell cycle in real time.

In keeping with the mainly retina-centric nature of this session Rod Bremner wrapped the session up by showing how the eye is also an excellent model system in which to study the susceptibility to and onset of tumours. Using the mouse as a model system he described his elegant genetic strategies to unravel how the members of the Retinoblastoma (Rb) family of proteins interact with various components of cell cycle and signaling pathways to carry out their vital functions as tumour suppressors.

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A few months ago we ran a survey on the Node to ask how you used the site, and if you had any suggestions. First of all, a big thank-you to all of you who took the time to answer our questions. As promised, we held a random draw among the survey participants: the winner was Gregory Shanower and he has been sent some gifts from Development and the Node. Congratulations!

So what did the survey tell us?

The complete report is 13 pages long. We’ll spare you that, but there were some recurring themes that we thought you might be interested in, so here is a short summary of the results – just to give you a brief idea of what we’ll be focusing on in the near future:

Who is reading the Node?
Let’s start by shattering a myth. One of the biggest misconceptions about the Node is that it’s “only for young people”. We hear this comment regularly but we now have the data to prove that it is not true. As the pie chart below shows, there is an equal distribution of PhD students, postdocs and PIs reading the Node. (Considering that in absolute numbers there are far more PhD students and postdocs than there are PIs, this means that, relatively speaking, the Node seems to be more popular among PIs than among younger researchers!)

Other facts about you, the Node’s readers:
* Almost 90% of the Node audience identifies as developmental biologists, but many also have interests in cell biology, genetics, stem cell research, or other areas of the life sciences.
* One in four Node readers has heard about the Node from a friend or colleague. Thank you for talking about us!

What are the most popular features on the Node?
Aside from the main content on the Node, the job postings and event listings are the most popular features. This is as good a place as any to remind everyone that you can add jobs and events if you have a Node account. You’ll receive posting instructions once your account is approved. Speaking of which…

Writing for the Node
About a third of the survey respondents has written posts or comments on the Node, posted job ads, or added events. Almost as many people indicated that they had not written anything on the Node, but would like to write something.

Of the people who had never posted on the Node, some said they didn’t have time, or that they were not confident about making their opinions public. Many others simply didn’t know what to write about, or didn’t know that they could, so we’ll be doing a bit more in the future to make it clear that anyone can post and we’ll try to set up a resource (perhaps an opt-in mailing list) to offer topics and ideas for Node posts for enthusiastic (current and future) Node contributors who suffer from writers block.

Keeping up with the Node
One of the most striking things that we found in the survey is that a lot of you are simply not able to keep up with everything on the Node, and more than half of you simply scroll through posts on the homepage. One immediate solution is that we’ll start doing monthly summary posts, highlighting some of the content from earlier that month. Here is the first one, for September 2011. We’ll also see if there is anything we can do in terms of layout and presentation, but that will be a more long-term plan.

Topics
Finally, we received a lot of great suggestions for features and for topics for future Node posts, and we’ll try to get as many of those on the site as we can. (Of course everything depends on people actually writing content, so it’s ultimately up to you.)

Several people made a suggestion that was quite straightforward and that we’ve already started in response to these suggestions: to do regular round-ups of upcoming deadlines for meetings, scholarships or grants. It’s hard to ensure such updates are complete, so if you see one of these posts and know of another deadline, feel free to post it yourself, or leave a comment on a previous deadline post. You don’t need an account to comment, and your email address will never be public.

If you have any questions about the survey we ran, or if you have some additional suggestions for the Node, feel free to leave a comment below.

(4 votes)

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An NIH-funded postdoctoral position is available in the Nascone-Yoder laboratory at North Carolina State University (Raleigh, NC, USA) to study the role of non-canonical Wnt/PCP signaling in Xenopus gut morphogenesis. The successful applicant will elucidate the cellular and molecular basis of gut tube lumen formation, gut tube elongation and rotation, and/or digestive epithelial morphogenesis. 

We are seeking a self-motivated Ph.D. scientist with graduate training in cell and/or developmental biology, and at least one peer-reviewed publication.  A strong background in molecular biology must be demonstrated. Experience in Wnt signaling, aquatic animal models, immunohistochemistry, organ culture, and/or confocal microscopy is also highly desirable.

Interest in working in a multidisciplinary environment is a plus: other research in the lab involves drug discovery through small molecule screening [Chemistry & Biology, 18(2): 252-263], the development of photoactivatable loss-of-function technologies [J Am Chem Soc., 132(44):15644-50], and the evolution of unusual gut morphologies in non-model frog species [Science, 331(6015): 280-281].

For more information, please visit:       http://www4.ncsu.edu/~nmnascon/

North Carolina State University is situated in the heart of the Research “Triangle” (as delineated by the three relative locations of NCSU, Duke University & University of North Carolina at Chapel Hill), where many of the country’s leading technology, research and pharmaceutical companies thrive.  The Nascone-Yoder lab is located in the Department of Molecular Biomedical Sciences at the NCSU College of Veterinary Medicine, currently ranked 3rd among the top veterinary colleges in the nation, with state of the art resources for both basic and clinical research.

Review of applications will begin immediately and will continue until the position is filled. Please send a CV, including a list of three references, and a statement of research interest by email to:   nmnascon[at]ncsu.edu

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This year’s Nobel Prize in Physiology or Medicine has just been announced, and the winners are Bruce Beutler (The Scripps Research Institute), Jules Hoffmann (University of Strasbourg) and Ralph Steinman (Rockefeller University), for their research on the immune system. [Update 14:04: Just heard that Ralph Steinman died of pancreatic cancer this weekend. Committee still deciding whether to give him the award – they are not given posthumously, but committee picked winners before he died.]

Steinman discovered dendritic cells, while Beutler and Hoffmann studied the genetics behind immunity. At first glance, it does not seem to be directly related to developmental biology, but a closer look at Hoffmann’s and Beutler’s work in particular suggests differently:

Hoffmann started out studying developmental biology, and early in his career he researched the role of steroid hormones on insect development. However, if you look at his publication history, it shifts toward immunology in the mid-eighties. In 1987 he still published on locust development, but just a year later he had a paper on insect immunity, followed by many others.

Even when Hoffmann focused predominantly on immunology later in his career, developmental biology found a way to catch up with him.

In a 1996 paper in Cell, Hoffmann’s lab showed a connection between Drosophila development and immunity. Specifically, they found that Toll signalling pathways was involved in antifungal defence in flies. While Toll was already known at that point for its role in dorsoventral patterning, thanks to Christiane Nüsslein-Volhard’s work, Hoffman was the first to identify the role of Toll in the fly’s innate immune response. Soon after this, other groups, including Beutler’s, identified Toll-like receptors in mammals.

That’s not the only developmental connection to this year’s Nobel Prize. Of course, to have a functioning immune system, you need to form the components of that system, and this has been a recent area of interest for Nobel Laureate Bruce Beutler. A Nature Immunology paper from earlier this year describes the requirement of the ATPase ATP11C in B cell development in adult (but not fetal) bone marrow. The paper describes the identification of X-linked mutations in mice that interfere with B cell development, and linked the phenotype to recessive mutations in Atp11c, which encodes a P4-type ATPase. The precise molecular pathways by which ATP11C regulates B cell differentiation are yet to be determined, showing that even for Nobel Prize winners there is always more left to be discovered…

References:
LEMAITRE, B., NICOLAS, E., MICHAUT, L., REICHHART, J., & HOFFMANN, J. (1996). The Dorsoventral Regulatory Gene Cassette Controls the Potent Antifungal Response in Drosophila Adults Cell, 86 (6), 973-983 DOI: 10.1016/S0092-8674(00)80172-5

Siggs, O., Arnold, C., Huber, C., Pirie, E., Xia, Y., Lin, P., Nemazee, D., & Beutler, B. (2011). The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow Nature Immunology, 12 (5), 434-440 DOI: 10.1038/ni.2012

(2 votes)

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What was new on the Node this month? Here are a few of the highlights from September:

EMBO meeting
Natascha Bushati attended the EMBO meeting, and wrote several posts as one of their certified bloggers, including two interviews that are definitely worth a read: one with Janet Rossant, and a joint interview with Eric Wieschaus and Marcos González-Gaitán. Below are some quotes, but there’s much more in the full interviews.

“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?” – Janet Rossant

“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.” – Marcos González-Gaitán

“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.” – Eric Wieschaus

Japan
This past month saw several posts about (research from) Japan: Bruno Velutini summarized turtle shell development research from the Kuratani lab, Paul O’Neill featured a new study on transparent mice, also from the RIKEN institute, and Mubarak Hussain Syed wrote about the developmental neurobiology course he took this summer in Okinawa.

 
Careers
* Thomas Butts expressed his concern about the future of UK science careers in his contribution to the latest Science is Vital campaign.
* An article summarizing the Node’s alternative careers posts was published in Development (and on the Node) at the start of the month.
* Finally, as always, check out the job listings on the Node for the latest openings in labs around the world.

Everything else:
Still want more? Browse the full September archive of posts to see the rest of the month!

(2 votes)

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Fully Funded PhD Places available in Developmental Biology and Neuroscience

Syracuse University, New York, USA.

Interneuron specification in the zebrafish spinal cord.

The Lewis Lab recently moved to Syracuse University from Cambridge University in the UK. We use Genetics, Cell Biology and Developmental Biology to investigate how the correct number and pattern of different neurons forms in the vertebrate spinal cord, and how these neurons acquire their specific characteristics and functions.

PhD Projects are available to investigate the roles of specific regulatory genes (Transcription Factors) in determining different neuronal characteristics (such as neurotransmitter phenotypes and axon morphology) in the zebrafish spinal cord.
We primarily use zebrafish embryos as a model system, as the embryos develop outside the mother and are transparent and their relatively simple nervous system facilitates studies of neural circuitry and function. We use GFP lines (see picture) to study neurons in live and fixed embryos. As most of the genes involved in spinal cord development are conserved between vertebrates, the insights that we gain should be widely applicable, including to humans.
See http://biology.syr.edu/faculty/lewis/lewis_research.htm for more details
Application Deadline:
Deadline for August 2012 admission is January 2012.
Applications will be considered in the order that they are received – so if you are interested please apply soon! We will start assessing applications in December 2011.
Notes on Funding and PhD Program
Funding will be a mixture of teaching and research assistantships and is guaranteed for 5 years.
Students usually rotate in 3 different labs and then choose a lab for the PhD.

Information on other labs in the department can be found here: http://biology.syr.edu/directories/fac_dir.htm
For more details on the graduate program see http://biology.syr.edu/grad/graduate.htm
Syracuse has its own airport (15 minute drive from downtown) and is close to Toronto, New York City, Philadelphia, Montreal as well as the natural beauty of Upstate New York (Niagara Falls, The Finger Lakes, Adirondack lakes and mountains).
Syracuse University shares a campus with SUNY Upstate Medical University that has active research programs which include Cell Biology, Developmental Biology and Neuroscience http://www.upstate.edu/research/research_dept.php and the Lewis Lab is also part of their graduate program in Neuroscience (for which there is a separate application).

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It’s the end of the month, which means it’s time to download next month’s desktop calendar. Put it on your own computer and/or on the computers in your lab. There, now you’re all ready for October!

Mouse embryo showing Wnt1/Cre-YFP transgene (yellow), 2H3 antibody (red), and DAPI (blue). This image, taken by Elsa Denker of the Sars International Centre for Marine Molecular Biology, was one of the candidates in the fourth Development cover image voting round of images taken at the 2010 Woods Hole Embryology course.

Visit the calendar page to select the resolution you need for your screen. The page will be updated at the end of each month with a new image, and all images are chosen from either the intersection image contest or from the images we’ve featured from the Woods Hole Embryology 2010 course.

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-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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