The MRC has now launched its first, cross-Board Call for Pump Priming Awards for preliminary research using IMPC knockout mice (http://www.mrc.ac.uk/funding/browse/pump-priming-awards-for-preliminary-research-using-impc-knockout-mice/).

The aim of this initiative is to capitalise on MRC’s (and others’) investments in the International Mouse Phenotyping Consortium (IMPC) (https://www.har.mrc.ac.uk/research/large-scale-functional-genomics/international-mouse-phenotyping-consortium-impc) and make best use of the resources, data and tools available. The expectation is to provide small, flexible awards to allow the take-up and use of the existing phenotyped and banked knockout lines and resources to support UK research.  It is expected that this will catalyse more ambitious studies in the future.

Applications are invited from UK-based research groups to receive, via the MRC’s Mary Lyon Centre (http://www.har.mrc.ac.uk/about/mary-lyon-centre), knockout mice produced by the IMPC, and undertake early biological investigations that build on existing research expertise and underpin longer-term research goals.

This Call will run in May 2016 and 2017, with 10-25 awards made in September 2016 and 2017.  Awards will be of 1-2 years’ duration and 20-40k in value.

The deadline for this year’s applications is 4pm on 8th July 2016.

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For the first time, a reference mouse embryo atlas has been created using HREM image data. For other embryo imaging methods such as micro-CT, a reference embryo atlas has previously been shown to be the basis of automated phenotyping (Wong et al, 2014). This new work (a collaboration between the DMDD programme and the Mouse Imaging Centre in Toronto) is a proof of principle for automated phenotyping of HREM data, which can now be tested in more detail.

COMPARING LIKE WITH LIKE

In order to phenotype an embryo, we need to compare it to another embryo that we consider to be normal. With histology this can be very difficult, as it’s virtually impossible to take exactly the same slice through two embryos.

So this leads to the question ‘have I really observed a phenotype, or am I simply looking at a different part of the embryo?’

The ideal scenario for a phenotyper is to have exactly equivalent slices of anatomy to compare. They can then do a direct visual comparison, or an algorithm can be used to do a statistical comparison, therefore automating the process to some degree.

A REFERENCE EMBRYO ATLAS

Using a technique previously employed with micro-CT data (Wong et al, 2012), the team have created a reference embryo atlas from HREM data. The atlas can be used to find these equivalent sections of anatomy.

21 wild-type embryo image stacks were merged together to give an unbiassed ‘average embryo’. Every possible pair of embryos was compared in terms of displacement. The embryos were then combined together so that the displacement for all embryos to join the atlas was a minimum. This technique avoids giving undue weighting to any one embryo in the average.

As HREM data is so large, the resolution was scaled back first to make the computation feasible.

For each individual embryo, a different deformation field is needed to bring the image into alignment with the average. The inverse of this field can then be used to propagate back from any plane in the reference embryo to a section of the original input embryo.

This means it’s possible to find equivalent embryo sections to compare, ensuring that any differences observed are much more likely to be genuine phenotypes.

It’s important to note that these sections are never planes but crinkly slices through the embryo. This means that the sections couldn’t have been identified by manually scrolling through the image stacks.

AUTOMATED PHENOTYPING

Automated selection of equivalent embryo sections is the starting point for automated phenotyping. Given the time-consuming nature of phenotyping embryos, and the large task of phenotyping many mouse lines, automated phenotyping is an attractive prospect to many. It can act as a guide – a primary screen to highlight areas of interest to manual phenotypers.

The next step, then, is to compare other HREM embryo data with this reference atlas.

The results of automated primary screens are typically presented as a heatmap (Wong et al, 2014), highlighting areas of interest. The authors showed a proof of principle for an automated primary screen of HREM data by separating the embryos into male and female groups. After selecting equivalent sections through the gonads to compare between the two groups, they were able to automatically distinguish statistically significant differences in this region.

This is an exciting result for the future of automated phenotyping of HREM mouse embryo data, which will be tested much more extensively over the coming months.

This post originally appeared on the DMDD blog, Annotations (blog.dmdd.org.uk).

DMDD is a systematic study of embryonic-lethal mouse gene knockouts, and provides a database of high-resolution image and phenotype data – a valuable resource for both developmental biologists and clinicians. Visit the website to find out more: dmdd.org.uk

READ THE FULL PAPER

R. Mark Henkelman¹, Miriam Friedel¹, Jason P. Lerch¹, Robert Wilson², Tim Mohun² (2016)
Comparing homologous microscopic sections from multiple embryos using HREM
Developmental Biology [Epub ahead of print], DOI: 10.1016/j.ydbio.2016.05.011

¹ Mouse Imaging Centre (MICe), Hospital for Sick Children, University of Toronto, Toronto, Canada
² The Francis Crick Institute Mill Hill Laboratory, London, UK

REFERENCES

M. D. Wong¹, Y. Maezawa², J. P. Lerch¹, R. M. Henkelman¹ (2014)
Automated pipeline for anatomical phenotyping of mouse embryos using micro-CT
Development, DOI: 10.1242/dev.107722

¹ Mouse Imaging Centre (MICe), Hospital for Sick Children, University of Toronto, Toronto, Canada
² The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada

M. D. Wong^1,2, A. E. Dorr^1,3, J. R. Walls⁴, J. P. Lerch^1,2, R. M. Henkelman^1,2 (2012)
A novel 3D mouse embryo atlas based on micro-CT
Development, DOI: 10.1242/dev.082016

¹ Department of Medical Biophysics, University of Toronto, Toronto, Canada
² Mouse Imaging Centre (MICe), Hospital for Sick Children, University of Toronto, Toronto, Canada
³ Sunnybrook Hospital, Toronto, Canada
⁴ Regeneron Pharmaceutecals, Tarrytown, USA

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A 15 months postdoctoral position is available at the Observatoire Océanologique de Villefranche-sur-Mer -LBDV (UPMC – Sorbonne Universités). We are seeking a highly motivated and passionate researcher to join a 5-years international project, DEVODIVERSITY, funded by the French Agence Nationale de la Recherché (ANR) and the São Paulo Research Foundation (FAPESP).

By using molecular and cell biology, NGS transcriptomic, genomic, and ecological approaches, a multidisciplinary consortium led by two teams, the Tiozzo Lab at the Villefranche-sur-Mer Developmental Biology Laboratory in France (CNRS-UPMC), and the Brown Lab at the Istituto de Biociências in Brazil (USP), will study the evolution of regeneration, asexual reproduction, and clonality in several species of ascidians (Urochordata), and examine how ecological factors affect distribution ranges, evolution of life cycles and developmental strategies. DEVODIVERSITY has the following main aims:

1. To resolve the phylogenetic relationships and evolutionary transitions between strict sexual reproduction to budding and high regenerative abilities among Styelidae (Ascidiacea).
2. To provide a coupled morphological and ecological understanding of asexual propagation (budding). We will generate detailed anatomical and developmental descriptions of budding processes, and explore if and which environmental conditions are associated with the use of particular budding modes.
3. To compare gene pathways involved in stem cell functions or trans/de-differentiation of budding and regenerative processes by the generation and in silico analyses of transcriptomic data.
4. To launch a comparative genomic approach study in order to better understand the evolution of a major life history transition in marine chordates, in particular the evolutionary transition from sexual to asexual propagation.

The candidate will be mainly based at the LBDV (Villefranche sur Mer, France) and may have the opportunity to do laboratory and fieldwork in both countries.

It is ESSENTIAL:

• A doctoral degree in animal biology, evolutionary biology or related disciplines.
• Demonstrated experience in molecular biology, organismal biology and at least bases of bioinformatics and biostatistics.
• Enthusiasm and genuine commitment to research work.
• Demonstrated ability to undertake independent research, flexibility and problem solving skills.
• Excellent communication skills in English spoken/written.
• Ability to collaboratively work on a team.

Expertise in phylogenomics and transcriptomics is highly desirable but not mandatory. The LBDV has an international working environment, speaking French is not required but it would be a plus.

The applicant should contact directly Dr. Stefano Tiozzo (tiozzo@obs-vlfr.fr) providing a letter of interest, a CV and the contact of three potential referees. Please, add “DD_postdoc” on the subject of your email. Applications review will continue until the position is filled. Starting data could be any time from September 2016.

Contacts

Stefano Tiozzo (tiozzo@obs-vlfr.fr): http://biodev.obs-vlfr.fr/~tiozzo/tiozzo-lab.

LBDV: http://biodev.obs-vlfr.fr/en/index.html

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I am hugely grateful to the Journal of Cell Science and the Company of Biologists for awarding me a traveling fellowship to visit the laboratory of Dr Guillermo Velasco at Complutense University in Madrid, Spain. During this visit I gained a greater understating of the skills and techniques used to manipulate autophagy regulatory pathways within melanoma stem-like cells, as well as knowledge of autophagy regulation within cancer.

Cutaneous malignant melanoma is the most aggressive form of skin cancer and despite the recent introduction of targeted therapeutics to treat the disease, relapse is common and there remains no effective cure for metastatic melanoma. Therefore, an improved understanding of the underlying biological mechanisms mediating development and progression of melanoma is desperately required. A potential therapeutic approach may be to target melanoma stem-like cells that sustain tumour growth and contribute to drug resistance. Stem-like progenitor cells from other cancers have been shown to use autophagy, the principle lysosomal mediated mechanism for the breakdown and recycling of damaged proteins, for survival. Therefore, as autophagy is also known to be important for melanoma growth, the current project aims to test the hypothesis that melanoma subpopulations that display a stem-like phenotype use autophagy for tumour maintenance, invasion and survival.

The trip to Dr Velasco’s lab allowed me to learn specific practical techniques for the identification and characterisation of cancer stem cells, as well as gain knowledge of autophagy regulation from experts in the field. During my time in Madrid I met a number of very interesting people who I hope will remain close collaborators in the future. Also, the experience of living and working in such a cosmopolitan city as Madrid is one that I can whole heartedly recommend to anyone!! It certainly is a fantastic city and I can’t wait until the next time I can visit.

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2nd Postdoc Position in Evo-Devo and Macroevolution

Hiring Organization:
Howard University

Date Posted:
2016-05-19

Position Description:
Postdoctoral Position in Evo-Devo and Macroevolution

Apart from the position posted a few days ago, we are happy to announce that a 2nd postdoctoral researcher is sought to join the Rui Diogo lab (www.ruidiogolab.com), at the Howard University College of Medicine, Department of Anatomy (Washington DC). For more details on the research done at the lab, and the papers/chapters/books published in recent years, see also:
https://www.researchgate.net/profile/Rui_Diogo
Diogo’s books: http://www.amazon.com/Rui-Diogo/e/B001JS2K96

The main difference between this position and the one previously announced is that the position will not be related to anatomical networks nor building websites. We are therefore interested in a candidate that will have the ability to:

1) contribute to uncover evolutionary and developmental mechanisms underlying both hard tissue (cartilages and bones) and soft tissue (mainly muscles) formation and patterning during ontogeny of a wide range of vertebrate taxa. Some of the issues and broader questions in which we are particularly interested include: the parallelism between ontogeny and phylogeny, the remarkable similarity between the hard and particularly the soft tissues of the upper and lower limbs of tetrapods, the importance of evolutionary reversions/neotenic events, the study of birth defects in human and non-human primates and their implications for medicine and for the understanding of evolutionary biology, and the regeneration of hard and soft tissues in key vertebrate taxa. For more information about these subjects and about other issues being studied in the lab, please see www.ruidiogolab.com.

2) help write review papers and books on the broader macroevolutionary topics covered above and other topics, and, by doing this you can relatively rapidly get a substantial experience in publishing in top journals and monographs.

In summary, this will be a position in a very productive lab, in which there is a relatively high independence, where the drive of the postdoc is essential to make her/him more productive, taking advantage of the broader scope and numerous collaborations of the lab. Contrary to the previously announced position, you will thus more involved in lab evo-devo research and in writing and publishing.

There are funds available for one year, starting fall (September) 2016, with the hypothesis of extending the position for two years, in case of excellent results and fit within the lab, i.e. the second contract depending on the productivity, interest and dedication of the candidate. There are possibilities to continue being part of the lab after the two-year period of the post-doc position. The post-doc will also have the opportunity to learn, and potentially to then become an instructor/faculty of human gross anatomy; this will further allow him/her to also postulate for faculty positions in medical schools in the DC area (including Howard University) as well as in other regions.

Interested candidates should send a CV including research interests, a list of publications and the names and contact information for three references to Rui Diogo, at rui.diogo@howard.edu. Please write “post-doc in Diogo’s lab” followed by your last name in the email subject.

Howard University is a historical University situated in the center of Washington DC, which is a beautiful, green and enjoyable city with numerous cultural and outdoor activities. The Department of Anatomy provides a prosperous, resourceful and multidisciplinary environment for biomedical research, includes faculty with a broad experience in developmental biology, paleontology, neurobiology, comparative anatomy and medicine. We have strong ties with surrounding institutions, particularly with George Washington University, and the candidate will probably have the opportunity to do part of his/her research at those institutions and thus to expand his/her knowledge and academic connections.

Qualifications/Experience:
The successful candidate will have a PhD degree with a broad experience in developmental biology (e.g., doing/using developmental techniques such as antibody staining, in situs, and cell tracing, among others) and/or evolutionary biology, and hopefully both, backed by publications in peer-reviewed journals, and ideally also some experience in comparative anatomy. He/She will have the skills and motivation to pursue a career in research, be interested in studying and comparing a wide range of taxa and various model organisms and in discussing various evolutionary and developmental issues, and be able to fulfill at least some, and ideally all four, items listed above.

Contact Information:
Rui Diogo
E-mail Address:
rui.diogo@howard.edu

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How on earth do we turn into a living, breathing, singing, speaking being, from just the fusion of two cells? Development is fascinating and mysterious. Stem cells are one component of how this intricate process unfolds, allowing the embryo to not have every type of cell from the start.

Imagine if the only way our bodies could form a brain, a liver, a heart, is if the embryo started out with little batches of each type of cell. Instead, stem cells make it possible to start with just one ‘flavour’ of cell, and turn that into the many cell types needed to make a fully formed human.

In order to take full advantage of stem cells, we need to understand development. What signals are these stem cells sending and receiving to tell them to become brain or liver or heart?

In a collaboration between Harvard University and Semmelweis University in Budapest, Nandor Nagy and his team used bird embryos to study the development of a special part of nervous system devoted to controlling our gut. The literal manifestation of the term, ‘gut instinct,’ the so-called enteric nervous system is an extensive network of ‘gut-brain’ cells wrapped around our gut.

To help answer the huge question of how this ‘second brain’ of ours develops, Nagy and his colleagues honed in on the role of one specific molecule, called sonic hedgehog (Shh), which is crucial to development in humans and many other creatures. Specifically, they wanted to look at how Shh influences the cells around the gut to turn into ‘gut-brain’ cells or not.

To visualize the effect of Shh, they took thin slices of the bird embryo’s gut and added fluorescence molecules that showed whether the ‘gut-brain’ cells were in early or late stages of development. The later stage they were in, the more Shh would be shown to push their development forward.

The red fluorescence shows early stage, whereas the green shows late. Adding Shh, in the right column, shows more green fluorescence, but the same amount of red, indicating that Shh pushes the cells into later stages.

In the span of just a few hundred words we have narrowed in on the effect of one molecule on one type of cell, and how we can visualize this. This story attests to the power of images in answering big questions, by zooming way in to the level of microscopic cells.

——

Further reading: What’s in the name? Pathways in development

Credit

Nagy, Nandor, et al. “Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix.” Development 143.2 (2016): 264-275.

Sonnenburg, Justin and Erica Sonnenburg. “Gut feelings- the “Second Brain” in our gastrointestinal systems.” Scientific American (2015).

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POSTDOCTORAL POSITIONS are available to study different aspects of lymphatic biology in health and disease, including the cellular and molecular mechanisms controlling the development of the of the lymphatic vasculature in mice, endothelial cell plasticity and reprogramming, as well as different aspects of lymphatic function in metabolic diseases. Highly motivated individuals who recently obtained a PhD. or MD degree and have a strong background in molecular, vascular and developmental biology are encouraged to apply. Interested individuals should send their curriculum vitae, a brief description of their research interests, and the names of three references to:

Guillermo Oliver, PhD (guillermo.oliver@northwestern.edu)

Director Center for Vascular and Developmental Biology

Northwestern University Feinberg School of Medicine

303 East Superior Street, 10-107

Chicago, Illinois 60611

Phone: 312-5031651

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Here are the highlights from the current issue of Development:

How the zebrafish got its tail

Posterior axis elongation is a crucial process during metazoan development. In principle, axial extension can be driven either by tissue growth or by tissue rearrangement – or by a combination of the two. In vertebrates, studies based primarily on chick and mouse have suggested that the presence of a posterior proliferative zone is key for driving axial elongation. Here (p. 1732), Ben Steventon and colleagues assess the relative contribution of volumetric tissue growth versus tissue deformation (lengthening along one axis while narrowing in the other) to posterior body elongation in the zebrafish. During early phases, elongation proceeds without growth and with minimal cell proliferation. At later stages, cell proliferation is confined primarily to the segmented region of the embryo and not to the elongating unsegmented tailbud. Thus, convergent extension-like movements, involving cells entering the posterior trunk from more lateral positions, are the major driving force of elongation in the zebrafish. Through comparative analyses in other vertebrates, the authors’ data suggest a correlation between posterior volumetric growth – as seen in dogfish and mouse but not lamprey or zebrafish – and nutrient availability during embryogenesis.

Navigating the brain: the many paths of the interneurons

In the mouse forebrain, interneurons (INs) are born in the ganglionic eminences and preoptic area, and migrate from there to the cortex and other brain regions. The medial ganglionic eminence produces most INs of the neocortex – particularly the early born ones – whereas a minority of later-born cortical INs, as well as INs of other brain regions, derive from the caudal ganglionic eminence (CGE). What specifies the different populations of INs and how they reach their targets, is still incompletely understood. Michèle Studer and colleagues now (p. 1753) analyse IN migration from the CGE, finding that, in addition to the well-known caudal migratory stream (CMS), populations of INs also migrate rostrally by taking medial and lateral paths (the MMS and LMS, respectively). INs in the different paths appear to express different subsets of transcription factors and give rise to distinct sub-populations of mature INs. The authors identify the COUP-TFI nuclear receptor as a key regulator of identity and fate of the MMS and LMS INs. These data uncover an unexpected complexity in the migratory paths of CGE-derived INs that might be crucial for defining the huge diversity of mature IN types in the brain.

Head development under hypoxia

The early amniote embryo develops in a hypoxic environment: until blood circulation commences, oxygen availability in the developing tissues is low. What consequences does this have for development? On p. 1742, Nobue Itasaki and co-workers investigate the role of the hypoxia-responsive HIF pathway in regulating cranial neural crest cell (CNCC) production in the chick – which normally occurs in a hypoxic environment. They find that, upon embryo culture under normoxia, fewer CNCCs emerge from the neural tube; this phenotype can be rescued upon drug-induced activation of the HIF-1α pathway. Consistent with this, the authors observe reduced expression of known markers and regulators of migratory neural crest – several of which have previously been implicated as HIF-1α targets. It therefore appears that hypoxia is necessary for normal CNCC production, but is it sufficient to induce ectopic CNCCs? Activation of HIF-1α at later stages, after blood circulation has normally commenced, can induce CNCC production in in vitro explants, though only weak effects are seen in embryos. These data highlight the importance of the hypoxic environment for normal cranial development and imply that the initiation of blood circulation might have broad developmental consequences related to oxygen availability and HIF signalling.

Coactivator complexes in the spinal cord

In the vertebrate spinal cord, the LIM-homeodomain transcription factors Isl1 and Lhx3 act in concert with the linker protein NLI to regulate neuronal differentiation: Lhx3/NLI complexes promote V2a interneuron fate, whereas Lhx3/Isl1/NLI complexes direct motor neuron differentiation. However, how these complexes mediate transcriptional activation is still poorly understood. Soo-Kyung Lee and co-workers now (p. 1721) elucidate a role for the single-stranded DNA binding proteins Ssdp1/2 in this process. Ssdps are known to interact with NLI in various contexts and have been implicated as possible components of LIM-containing complexes. Here, the authors show that Ssdp1/2 interact with Lhx3, Isl1 and NLI, and that they are required for efficient activation of target genes – both in vivo and in vitro. In both chick and mouse, Ssdp1/2 knockdown compromises V2a and motor neuron differentiation. Mechanistically, Ssdp1/2 appear to be involved in recruiting histone-modifying enzymes to Lhx3/Isl1 targets, triggering deposition of active chromatin marks. Thus, this work identifies Ssdps as key components of transcriptional regulator complexes in the spinal cord and it is likely that they play similar roles in other developmental contexts.

Making a mammary gland with Blimp1

Uniquely among mammalian organs, the mammary gland of the female undergoes repeated cycles of expansion and regression during pregnancy, suckling and weaning. The tissue must therefore be equipped with hormone-responsive mechanisms for cell proliferation, differentiation and subsequent destruction. Various populations of progenitor cells have been identified and characterised, but our understanding of their properties and lineages is still incomplete. Here (p. 1663), Elizabeth Robertson and colleagues identify the transcriptional repressor Blimp1 as a marker of a progenitor population in the luminal compartment of the mouse mammary gland – rare in virgin females but expanding dramatically in pregnancy. They further demonstrate that Blimp1 is required for cell proliferation, polarity establishment and maintenance, and for the efficient production and secretion of milk components. While the mechanisms by which Blimp1 exerts these effects have yet to be elucidated, these data identify an important new regulator of mammary gland development and a new subpopulation of progenitor cells in the mammary epithelium.

PLUS:

Of sex and determination: marking 25 years of Randy, the sex-reversed mouse

On Thursday 9 May 1991, the world awoke to front-page news of a breakthrough in biological research. From Washington to Wollongong, newspapers, radio and TV were abuzz with the story of a transgenic mouse in London called Randy. Why was this mouse so special? The mouse in question was a chromosomal female (XX) made male by the presence of a transgene containing the Y chromosome gene Sry. This sex-reversal provided clear experimental proof that Sry was the elusive mammalian sex-determining gene. Twenty-five years on, Koopman, Sinclair and Lovell-Badge reflect on what this discovery meant for our understanding of how males and females arise and what remains to be understood. Read the Spotlight on p. 1633

An overview of mammalian pluripotency

Mammalian pluripotency is the ability to give rise to all somatic cells as well as the germ cells of an adult mammal. Here, Juan Carlos Izpisua Belmonte and colleagues provide a summary of mammalian pluripotency both in vivoand in vitro, and highlight recent and future applications of pluripotent stem cells for basic and translational research. Read the poster article on p. 1644

Neurogenesis in Cancun: where science meets the sea

In March 2016, meeting organizers Sebastian Jessberger and Hongjun Song brought together over 100 scientists from around the world to Cancun, Mexico to present the latest research on neurogenesis. Here, Jenny Hsieh and Chun-Li Zhang describe the exciting work that was presented and highlight some of the emerging themes from the meeting. Read the Meeting Review on p. 1649

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