SCHOOL OF BIOLOGICAL SCIENCES, UNIVERSITY OF EAST ANGLIA

PhD POSITION AVAILABLE

The role of microRNAs in neural crest development

MicroRNAs (miR) are short, non-coding RNAs around 22 nucleotides long. They block gene expression either by translational repression or by causing the degradation of the mRNAs they bind to. They are involved in controlling various mechanisms during development by regulating gene expression at the post-transcriptional level. Some are highly conserved amongst diverse organisms and many of them have highly specific spatio-temporal expression patterns during development.

The Neural Crest (NC) are multipotent cells that arise at the border between the ectoderm and the neural plate. They give rise to tissues such as craniofacial muscle, peripheral and enteric nerves and pigment cells. In adults NC derived tissues can give rise to neuroblastoma and melanoma. We have been interested in studying neural crest development for a number of years.

We have recently carried out a project determining the expression patterns in Xenopus embryos of 195 miRs by wholemount in situ hybridisation (WISH). Some of these miRs showed expression in the NC.

The aim of this project will be to further characterize the expression of these miRs in NC as well as using Next Generation Sequencing (NGS) to identify other miRs expressed in NC and to then look at the function of some of these during NC development and to identify the target mRNAs they bind to.

White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, Zon LI. (2011) DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 471:518-22

Muhammad Abu-Elmagd, Carla Garcia-Morales and Grant N. Wheeler (2006). Frizzled 7 mediates canonical Wnt signalling in neural crest induction. Developmental Biology, 298:285-298

Deadline for application November 30^th 2012

For further info contact Dr. Grant Wheeler

Email: grant.wheeler@uea.ac.uk

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Advent calendar
Thanks to everyone who has sent in suggestions for papers for the advent calendar. We’re still looking for a few more to take us to a complete set of 24, so if you read something really great that was published after December 2011, please let us know via email. We’ll need your submissions by November 22nd – that’s Thursday!

Site updates
We finally found (and squashed) the bug that was breaking our RSS feeds, and are now getting ready to implement the new site changes we’ve had ready to go for a few weeks. Before we do this (in the next week or so), we just wanted to give you another reminder about the fact that anyone who has had a post published on the site (including job ads) will now have a public profile page. That page will include the description that you have filled out in your biography, as well as a link to your personal or lab website. See this post for more information.

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       On the morning of Sunday, November 11^th, the world lost a great gentleman scholar – Professor Farish A. Jenkins, Jr of the Museum of Comparative Zoology, Harvard University. Farish was an anachronism in today’s world who would have relished in lengthy discourse with the great comparative anatomists of the mid 19^th century, his gold watch tucked neatly at home in the pocket of an English waistcoat. He had the admirable skill of speaking with equal measure of comfort and respect not only among the chairs of academic departments but also with his doe-eyed undergraduate advisees. But hidden only slightly beneath the surface of his genteel nature lay a delightfully off color sense of humor punctuated by a deep, hearty chuckle that was infectious in part because no one could help but be amused by how much he tickled himself.

     Farish earned his PhD in Geology at Yale where he entered the great world of paleontology. Always one to look beyond his boundaries of comfort, he sought out training in anatomy at the medical school because after all, these were more than rocks. They were once living, breathing things with movement and three-dimesional form before they were crushed to a flattened and barely articulated state. From his deep understanding of anatomy sprung forth a long and fascinating career in functional morphology that spanned the full spectrum of vertebrate taxa. In his later years, through close friendships with several of us in the embryo world, he developed an additional appreciation for the embryonic origins of adult form and function. So much so that his classic vertebrate anatomy course has been merged and reformatted, along with Dr. Arkhat Abzhanov, to embrace a developmental perspective. Farish was a magnificent instructor. His teaching profoundly impacted thousands if not tens of thousands of students who passed before his colorfully chalked boards – painstakingly laid out in the hours before each class. Even beyond the walls of the classroom, I can’t imagine anyone ever crossed Farish’s path without learning something.

       Farish unknowingly wrote his own tribute in his unscripted speech to the students at his recent Festschrift at Harvard: “This is for the students here, and those who would be students…you entering vertebrate biology whether with molecular systematic interests or organism interests, ecological interests, whatever your interests. You’ve got a great career. Why? Because you will take joy in two things. Here’s where the joys have come in my life. Discovery. When a discovery hits you, you’re looking at something and you don’t see it. And then all of a sudden you do see it. But you didn’t see it because you weren’t prepared to see it. You will make discoveries. Those will be days of your life’s highest elation, and it’s one of the most wonderful things that’s ever happened to me. Days of discovery…The other great happiness that is waiting for you as students is that you will become teachers…Doing something that is entirely happy and joyful. Because if you are good teachers, you will convey your enthusiasm, your love and your insight so that all of a sudden you turn out classes of people who really appreciate the natural world of organisms, and the phenomenon, the incredibly interesting phenomenon, of evolution. And this gives you great joy and gives them great joy…” 

       The days immediately following Farish’s “retirement” party in June were filled with meetings with all of his friend-colleagues to discuss future projects and fun left to be had. One retires from a job but not from a life’s passion. As such, Farish never really retired but continued to dig deeper and found joy in chasing that next discovery. In recent weeks he still took great satisfaction from teaching, beaming at me with pride when my confidence built to erase the carefully sculpted pencil lines of the master and replace them with my own mind’s representation of the bleached bones that we both inspected through his old dissecting microscope. His passing leaves a void but also an inspiration to carry on in his styling – even if none of us could quite pull off his style.

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Most folks think that our brains don’t produce any more neurons after we’re born, but thankfully they do!  A small subset of stem cells within the hippocampus gives rise to neurons in a region of the brain believed to be associated with learning and memory, and a recent paper describes the self-renewal properties and potential of these stem cells, and identifies the use of Sox1 as a marker for them.

The production of neurons continues throughout adulthood from two sources in the brain—from radial astrocytes in the subgranular zone (SGZ) in the hippocampus and along the lateral walls of the lateral ventricles in the ventricular-subventricular zone (V-SVZ).  Neural stem cells (NSCs) within the SGZ divide to produce mature neurons in the granular layer of the hippocampus, which has been suggested to play a role in learning and memory.  A recent paper in Development describes the potential of this NSC population, and identifies markers that can be used to identify these stem cells.  The transcription factor Sox1 is found throughout early central nervous system development, and according to Venere and colleagues, is found in the NSC population of radial astrocytes.  By lineage tracing these Sox1-positive radial astrocytes, Venere and colleagues found that these NSCs give rise to most, if not all, granular neurons and a small number of hilar astrocytes.  The number of Sox1-positive radial astrocytes declines with age, consistent with a decrease in neurogenesis.  Despite the decline in number, these cells remain transcriptionally active.  In the images above, Sox1 (green) is found in a subset of radial astrocytes (blue).  Sox1, Sox2 (red), and the radial astrocyte marker GFAP (blue) are all found in one subset of cells (arrowheads), while another subset of non-radial progenitor cells has both Sox1 and Sox2 markers (arrows).  Sox2 is known to have overlapping, but distinct, expression with Sox1 during development.

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Venere, M., Han, Y., Bell, R., Song, J., Alvarez-Buylla, A., & Blelloch, R. (2012). Sox1 marks an activated neural stem/progenitor cell in the hippocampus Development, 139 (21), 3938-3949 DOI: 10.1242/dev.081133

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Identifying gene expression signatures that underlay diversification of muscle cells using cell type specific genomic approaches in Drosophila

Muscle network in Drosophila embryos represents an attractive system for studying cell diversification. Each muscle displays a specific size, location, attachment points and innervation. Several studies including those of our group (Junion et al., 2007, Bataillé et al., 2010; reviewed in de Joussineau et al., 2012) have led to identify key factors that control specification of different types of muscles and acting downstream realisator genes. At the same time these studies revealed a need for designing cell type specific genome-wide approaches allowing a more global and unbiased view of cell diversification processes.

The recruited post-doctoral fellow will integrate an ambitious and innovative project designed to address this issue. The main objective of this study is to apply newly developed cell-specific approaches to perform transcriptional and ChIPseq analyses in subsets of embryonic Drosophila muscles. As an outcome, we hope to uncover realisator gene signatures that specify different subsets of muscles and in particular required for setting fusion programs, attachment and innervation of individual muscles.

From a more general point of view this study should provide insights into the logic of the genetic control of cell diversification as such.

We are searching for a highly motivated researcher who will join our team and interact with bioinformatician already working on this project. Experience in transcriptional profiling and ChIPseq approaches as well as in Drosophila developmental genetics will be considered as an advantage but is not a requirement.

Please consider that GReD Institute provides dynamic scientific environment and access to a large spectrum of facilities including up-to-date confocal imaging and Drosophila transgenesis platforms.

Position is available from the January 2013.

If you are interested please contact :

Dr. Krzysztof Jagla

Ladybird team

GReD, INSERM U1103, CNRS UMR6293,

University of Clermont-Ferrand

28, Place Henri Dunant

63000 Clermont Ferrand France

+33 (0)473178181

christophe.jagla@udamail.fr

www.gred-clermont.fr

Junion, G., Bataillé, L., Jagla, T., DaPonte, J.P., Tapin, R. and Jagla, K. : Genome-wide view of cell fate specification: ladybird acts at multiple levels during diversification of muscle and heartprecursors. Genes & Dev 2007, 21, 3163-80.

Bataillé L, Delon I, Da Ponte JP, Brown NH, Jagla K. Downstream of identity genes: Muscle-type specific regulation of the fusion process. Dev Cell, 2010, 19:317-328.

de Joussineau C, Bataillé L, Jagla T, Jagla K. Diversification of muscle types in Drosophila:upstream and downstream of identity genes. Curr Top Dev Biol. 2012, 98:277-301.

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What was your favourite paper in the fields of developmental or stem cell biology this past year?

We’re preparing a little feature on the Node for the month of December: an advent calendar with a new paper recommendation each day from December 1 to 24.

For this, we need your help! What was your favourite paper of the past twelve months?

To keep the calendar selections a surprise, we ask you to email your choice to thenode [at] biologists.com (or use the contact form). It would be great if you could also tell us, in one sentence, why you selected that paper. The deadline is November 22nd.

You can submit multiple papers, but NOT one from yourself or your lab. (Similarly, Development staff are not selecting Development papers as their own choice – but anyone else can!)

Papers you select should have been published after December 1, 2011. It doesn’t matter which journal it’s in, as long as the article covers a topic in developmental biology, stem cells, or a related area (evo-devo, developmental genetics, etc.) Don’t forget the first half of the year – it seems long ago, but I’m sure there were some great papers those months.

If we end up with more than 24 papers, we’ll make a final selection based on the diversity of suggestions we’ve received at that point.

We’re looking forward to showing you the full selection of Node reader-picked papers next month!

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Here at Development, and at our sister journal Disease Models and Mechanisms, we are currently advertising two editorial positions.

Within the Development team, we are seeking to recruit a new Associate Reviews Editor with special responsibility for the stem cell field – reflecting the journal’s increasing visibility in that area. Further details on this exciting opportunity are available on the jobs page.

DMM also have a position for a Scientific Editor, and you can find more information on this opening here. Applicants with previous editorial experience are particularly encouraged.

Both jobs will be based at the Company of Biologists’ office in Cambridge, UK, and both provide a fantastic opportunity to work with a small not-for-profit publisher at the heart of the scientific community.

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Scientific Editor Disease Models & Mechanisms
Based in Cambridge, UK

Joining a young journal in an expanding and important area of research, this is an exciting opportunity for a promising scientific editor to make a significant contribution to a growing open access journal serving a major new biomedical community.

The journal is entering the next phase of its development with the appointment of a team of academic editors, having been managed previously by a professional editor. As part of this evolution of the journal model, we will require the new scientific editor to be flexible in their areas of responsibility. Disease Models & Mechanisms publishes both primary research articles and commissioned front section material and we expect the scientific editor to take a role in both of these areas.

Since the journal serves both basic biomedical researchers and clinicians, applicants will have a PhD or MD with some relevant research experience, and a broad knowledge of model organisms and disease issues, and will ideally already hold an editorial role (we also provide on-the-job training).

Core responsibilities are expected to include:
• Support for the academic editors in their assessment and handling of primary research articles
• Commissioning, handling peer review and developmental editing of material for the front section of the journal
• Writing pieces for the journal, conducting interviews and preparing press releases
• Representing the journal at international conferences and within the wider scientific community
• Creative involvement in the journal’s development and marketing

The Scientific Editor will work alongside an experienced in-house team, and additional responsibilities may be provided for the right candidate.

Essential requirements for the job are enthusiasm, commitment, judgement, integrity and a mature attitude. Candidates should have excellent interpersonal skills, excellent oral and written communication skills, and a broad interest in research and the research community.

The position represents a unique opportunity to gain experience on an exciting new biomedical research journal and offers an attractive salary and benefits.

The Company of Biologists (www.biologists.com) is a not-for-profit organisation, publishing five journals in the biological sciences: Disease Models & Mechanisms, Development, Journal of Cell Science, The Journal of Experimental Biology and Biology Open. The organisation has an active programme of charitable giving for the further advancement of biological research, including travelling fellowships for junior scientists, contributions to academic societies and conferences, and a series of scientific workshops.

Applicants should send a CV along with a covering letter that states their salary expectations and summarises their relevant experience and why they are enthusiastic about this opportunity.
Applicants must be able to provide confirmation of entitlement to work in the UK.

Applications should be sent by email no later than 18th November 2012 to miriam@thecob.co.uk
Informal queries to Miriam Ganczkowski on +44 (0)1223 426 164.

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Associate Reviews Editor (Stem Cells) Development
Based in Cambridge, UK

Applications are sought for a new role of Associate Reviews Editor for the stem cell field at Development.

Joining an experienced, expanding and successful team, this is an exciting opportunity for a promising scientific editor to make a significant contribution to one of the major journals in the field of developmental biology. Development publishes primary research articles, reviews and other front section content. The journal is expanding its focus in the stem cell field, and is seeking to appoint a specialist editor to cover this growing area.

Applicants will hold a PhD, ideally in stem cell biology, although outstanding candidates with experience in other areas of developmental biology and with a strong interest in the stem cell field will be considered. Post-doctoral and/or previous editorial experience are highly desirable, although we will provide on-the-job training. The successful candidate will have a broad interest in science, the scientific community and publishing. Excellent interpersonal and literary skills, enthusiasm and commitment are also essential requirements for the position.

Core responsibilities:
• Commissioning, handling peer review and developmental editing of material for the front section of the journal
• Writing press releases, article highlights and material for Development’s community website ‘the Node’
• Representation of the journal at international conferences and within the wider scientific community
• Creative involvement in the journal’s development

The new Associate Reviews Editor will work alongside an experienced in-house team, including the Executive Editor and current Reviews Editor, as well as with our international team of academic editors. Additional responsibilities may be provided for the right candidate.

The position represents a unique opportunity to gain experience on a highly successful life-science journal and offers an attractive salary and benefits. The position will be based in our office in Cambridge, and the contract will be for a three-year period.

The Company of Biologists (www.biologists.com) is a not-for-profit organisation, publishing five journals in the biological sciences: the three established journals Development, Journal of Cell Science and The Journal of Experimental Biology, as well as two newer Open Access journals, Disease Models & Mechanisms and Biology Open. The organisation has an active programme of charitable giving for the further advancement of biological research, including travelling fellowships for junior scientists and contributions to academic societies and conferences.

Applicants should send a CV along with a covering letter that summarises their relevant experience and why they are enthusiastic about this opportunity, and states their salary expectations.

Applications should be sent by email no later than November 26th to miriam@thecob.co.uk
Informal queries to Miriam Ganczkowski on +44 (0)1223 426 164

Applicants must be eligible to work in the UK.

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Here are the highlights from the current issue of Development:

Dishevelled: the Notch-Wnt go-between

The Notch and Wnt signalling pathways are used during animal development to generate a diverse array of cell types. The two pathways often have opposing effects on cell-fate decisions but some cells receive inputs from both pathways simultaneously. In these circumstances, it is common for the receiving cell to exhibit a Wnt-ON/Notch-OFF response but how is this response generated? Now, on p. 4405, Keith Brennan and co-workers report that Wnt acts via Dishevelled, a key mediator of Wnt/β-catenin signalling, to inhibit the Notch pathway and that this crosstalk controls cell-fate specification during Xenopus epidermal development in vivo. Dishevelled, they report, binds and directly inhibits the CSL (CBF1, Suppressor of Hairless, Lag-1; RBPJκ in mice) transcription factors that mediate Notch signalling. Moreover, this crosstalk mechanism is conserved between vertebrates and invertebrates. Thus, by acting as both an activator of Wnt signalling and an inhibitor of Notch signalling, Dishevelled sharpens the distinction between opposing Wnt and Notch responses, thereby ensuring that robust cell-fate decisions are taken during development.

MicroRNA regulation of angiogenesis

Secreted signalling molecules regulate cellular communication across tissues during development. For example, during angiogenesis in zebrafish embryos, vascular endothelial growth factor (VEGF) secreted by muscle controls the expansion and remodelling of the vascular network. The precise regulation of VEGF expression in muscle cells is therefore essential for angiogenesis but how is this regulation achieved? On p 4356, Yuichiro Mishima, Antonio Giraldez and colleagues report that miR-1 and miR-206 (miR-1/206; two conserved microRNAs with similar sequences) negatively regulate angiogenesis during zebrafish development. The negative effect of miR-1/206 on angiogenesis, the researchers report, is mediated in part by direct regulation of VegfAa in muscle. Thus, masking the target sites for miR-1/206 in the 3′ UTR of vegfaa has a pro-angiogenic effect similar to that of miR-1/206 knockdown. By contrast, reducing the levels of VegfAa rescues the increase in angiogenesis produced by miR-1/206 knockdown. Together, these findings uncover a novel function for miR-1/206 in the control of developmental angiogenesis and highlight a key role for microRNAs as regulators of cross-tissue signalling.

HIF1α controls collagen secretion under hypoxia

The production of collagen – a major component of the extracellular matrix – depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as substrate. Cells that develop in hypoxic settings can nevertheless produce collagen during embryogenesis. Elazar Zelzer and colleagues begin to resolve this paradox on p. 4473 by identifying the transcription factor hypoxia-inducible factor 1 α (HIF1α) as a central regulator of collagen hydroxylation and secretion by chondrocytes in the hypoxic growth plate of developing mouse bones. The researchers show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of collagen. Hif1α, they report, drives the transcription of collagen prolyl 4-hydroxylase, which mediates collagen hydroxylation and its subsequent folding and secretion. Concurrently, Hif1α also maintains cellular oxygen levels, probably by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. This two-pronged mechanism, the researchers suggest, allows chondrocytes to secrete large amounts of collagen in the hypoxic environment of the growth plate.

Cycling towards sepal cell specification

During development, cell division and cell specification must be coordinated to ensure that the tissues and organs of the adult organism are the correct size and contain the right proportions of various cell types. Here (p. 4416), Adrienne Roeder and colleagues investigate how developmental regulators interact with the cell cycle in Arabidopsis sepals to create a characteristic pattern of outer epidermal cells in which elongated giant cells, which are produced by endoreduplication (DNA replication without cell division), are interspersed between small cells, which divide mitotically. They show that distinct enhancers are expressed in giant cells and small cells, which suggests that these cells have different identities as well as different sizes and ploidies. Several members of the epidermal specification pathway control the identity of giant cells, they report, which is established upstream of cell-cycle regulation. By contrast, endoreduplication represses small cell identity. Thus, suggest the researchers, cell type affects cell-cycle regulation but, in addition, cell-cycle regulation can control cell identity.

Epigenetic reprogramming egged on

The generation of cloned embryos by somatic cell nuclear transfer (SCNT) into enucleated mature oocytes is inefficient because epigenetic reprogramming is limited in these embryos. However, treatment of somatic nuclei with a cytoplasmic extract from germinal vesicle (GV) stage oocytes before SCNT is known to improve the efficiency of cloned mouse production. Now (p. 4330), Hong-Thuy Bui, Jin-Hoi Kim and co-workers use an extract from GV stage pig oocytes (GVcyto-extract) to investigate epigenetic reprogramming events in pig fibroblasts. The researchers report that fibroblasts treated with GVcyto-extract express the stem cell-associated proteins Oct4 and Nanog and re-differentiate into three primary germ cell layers in vitro and in vivo. Moreover, the use of donor nuclei treated with GVcyto-extract, they report, increases the number of high quality SCNT-generated blastocysts that exhibit levels of histone H3-K9 methylation and acetylation and Oct4 and Nanog expression similar to those in embryos fertilised in vitro. These results suggest that a combination of epigenetic reprogramming techniques might improve the efficiency of development in SCNT-generated embryos.

Notch pick and mix regulates lung development

In developing mammalian lungs, the terminal buds of elongating airways contain multipotent epithelial progenitors that give rise to the three major lung epithelial cell types: Clara, ciliated and neuroendocrine (NE) cells. Now, Mitsuru Morimoto and colleagues provide new insights into how Notch signalling regulates the distribution of these epithelial cell types in the airway (see p. 4365). Using stepwise removal of Notch1, Notch2 and Notch3 from developing mouse lung epithelium, the researchers show that Notch2 alone mediates the Clara/ciliated cell fate decision whereas all three receptors regulate NE fate selection in an additive manner. All three Notch receptors also additively regulate the size of the presumptive pulmonary neuroepithelial body (pNEB; NEBs are clusters of NE cells) through mutual interactions between NE cells and a population of SSEA-1 (stage-specific antigen 1)-positive epithelial cells that surrounds the pNEB. These and other results indicate that two different assemblies of Notch receptors control the number and distribution of lung epithelial cell types during lung organogenesis.

PLUS…

Drosophila neuroblasts: a model for stem cell biology

As part of the ‘Development: the big picture’ series, Homem and Knoblich explain why Drosophila neuroblasts, the stem cells of the developing fly brain, have emerged as a key model system for neural stem cell biology. See the Primer on p. 4297

Endocytic receptor-mediated control of morphogen signaling

Thomas Willnow and colleaugues describe how low-density lipoprotein receptor-related proteins (LRPs) constitute central pathways that modulate morphogen presentation to target tissues and cellular signal reception, and how LRP dysfunction leads to developmental disturbances in many species. See the Primer on p. 4311

Piecing together the vertebrate skull

As part of the ‘Development Classics’ series, Nicole M. Le Douarin discusses her 1993 Development paper, in which she and her colleagues used the quail-chick chimera system to decipher the embryonic origin of the bones of the head skeleton of the avian embryo. See the Spotlight article on p. 4293

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