PhD project title:

Non-genetic mechanisms of inheritance influenced by the maternal environment

Project description:

In the last few decades, it has been becoming increasingly clear that organisms can express phenotypes that are inherited in a non-Mendelian fashion. Studies in humans, for example, show that grandfathers who experienced dramatic diet fluctuations as children influenced the incidence of heart disease in their grandchildren. The mechanisms for transgenerational effects, however, are poorly known.

The aim of this project is to study the effect of maternal environment on sex determination of a species of nematode. In this nematode, if the mother smells a specific chemical, she will give rise mostly to hermaphrodites. Otherwise, the mother will produce mostly females. The student will investigate the mechanisms by which an odorant signal can change the epigenetic status of the germline, thereby influencing sex determination. This project will involve RNA sequencing of the germline of mothers that experience odorant stimuli. Mechanistic tests will be performed by genetic manipulation of the nematodes either by mutational analysis or RNA interference.

Key experimental skills involved:

The student will gain experience in analyzing large datasets derived from next-generation RNA sequencing, as well as standard methods in molecular biology and model systems, such as generation of transgenics and RNA interference.

References:

Kaati, G., Bygren, L. O., Pembrey, M. and Sjostrom, M. (2007). Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15, 784-790.

Jablonka, E. (2012). Epigenetic inheritance and plasticity: The responsive germline. Prog Biophys Mol Biol. xxx 1-0 (advanced online).

Chaudhuri, J., Kache, V. and Pires-daSilva, A. (2011). Regulation of sexual plasticity in a nematode that produces males, females, and hermaphrodites. Curr Biol 21, 1548-1551.

Shakes, D. C., Neva, B. J., Huynh, H., Chaudhuri, J. and Pires-daSilva, A. (2011). Asymmetric spermatocyte division as a mechanism for controlling sex ratios. Nat Commun 2, 157.

Contact details for application enquiries:

http://www2.warwick.ac.uk/fac/sci/lifesci/study/pg/research/phd/studentships/#SLS_PhD_Pires

http://www2.warwick.ac.uk/study/postgraduate/apply/

andre.pires@warwick.ac.uk

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Developmental biologists have long relied on the power of observation to understand how embryos develop. In addition, pharmacologic and genetic manipulation of embryos gives us clues as to the mechanisms involved in proper developmental processes. The ability to combine embryo manipulation with observation of embryonic development in real time has been possible for quite some time when using model organisms that develop externally, such as chicks, frogs and zebrafish. However, for those of us that use a mammalian model system, the technology to observe development in real time has lagged way behind. How we long for a way to watch organ systems develop and cell populations migrate and differentiate in the early embryo. While we have many sophisticated genetic tools to study these types of processes, we are limited to looking at simple “snapshots” of time based on when the embryos are dissected and fixed. The task of generating a robust confocal microscopy-based live imaging platform for early mouse embryos was taken on by R’ada Massarwa, a post-doc in the Niswander lab and the culmination of this work was recently published in Development (2013 Jan;140(1):226-36).

During the creation of this live imaging system, she chose to observe the process of neural tube closure, which occurs between days 8.5 and 10.0 of embryonic growth (E8.5-E10.0) in the mouse. Following dissection and experimental setup, the embryos are able to survive up to 16 hours of live imaging. Thus, by performing a series of experiments in which embryos were dissected at increasing somite stages, the entire process of neural tube closure was observed. This type of careful sequential experimentation also showed that the culture and imaging system did not interfere with the proper growth and movement of the tissues. The result: beautiful movies that not only show us how the neural tube develops, but also highlight all the exciting possibilities that this system brings to the study of early mammalian development.

We have been using this system to study neural tube closure, but there are many other tissues and organs that develop during these time periods (E8.5-E10.5) that are amenable to imaging including the heart, face, limbs and neural crest. By using tissue-specific Cre- recombinase reporter strains, the behavior of individual cell types can now be observed in real time in the early mammalian embryo. Also, combining fluorescent reporter strains with genetic knock-out strains and imaging the mutant embryos as the phenotype begins and progresses can provide a much better understanding of how the loss of gene function affects a developmental process. This system also provides access to the embryo itself for pharmacologic and physical manipulation. Overall, the potential for what can be learned using this live embryo imaging system is incredible. We are excited to share this technology with the scientific community and we look forward to seeing how all of you are able to use it to your advantage. Happy imaging!

Massarwa R. & Niswander L. (2012). In toto live imaging of mouse morphogenesis and new insights into neural tube closure, Development, 140 (1) 226-236. DOI: 10.1242/dev.085001

(5 votes)

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Every time a biologist drives pluripotent cells to differentiate into a specialized cell type, patients of all sorts of diseases, disorders, and injuries allow their hope to grow.  A research group recently reported how to drive differentiation of human pluripotent stem cells into medium-sized spiny neurons, the neurons that are some of the first to undergo degeneration in Huntington’s Disease.

hPS (human pluripotent stem) cells have the ability to differentiate into countless specific cell types, and can be either human embryonic stem cells or induced pluripotent cells.  hPS cells can generate various neuronal cell types, so their use in studying neurological diseases and regenerative therapies for such diseases is notable.  Huntington’s disease is an untreatable genetic neurodegenerative disease that typically begins with the degeneration of medium-sized spiny neurons (MSNs), neurons found in the basal ganglia region of the brain.  A recent paper in Development describes how hPS cells can be driven to an MSN fate.  Carri and colleagues began a combinatorial modulation of the pathways involved, beginning with BMP/TGFβ pathway inhibition.  About 20% of the neurons differentiated from hPS cells in these experiments are DARPP-32+/CTIP2+ MSNs also containing dopamine D2 and A2a receptors.  These resulting MSNs showed a firing pattern and neuromodulation identical to mature, authentic MSNs.  Carri and colleagues transplanted the hPS cell-induced neurons into the striatum of acid-lesioned rats, leading to their in vivo survival and differentiation towards an MSN fate.  In the images above, hPS cells were differentiated into neurons that contained DARPP-32 (green), a marker for MSN identity.

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

Carri, A., Onorati, M., Lelos, M., Castiglioni, V., Faedo, A., Menon, R., Camnasio, S., Vuono, R., Spaiardi, P., Talpo, F., Toselli, M., Martino, G., Barker, R., Dunnett, S., Biella, G., & Cattaneo, E. (2012). Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons Development, 140 (2), 301-312 DOI: 10.1242/dev.084608

(1 votes)

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We haven’t posted one of these in a while, but there are quite a few things coming up. Remember to also keep an eye on the calendar, and add events there.

Conference and course deadlines in the next few weeks:
January 14 – abstract submission deadline for the annual meeting of the Dutch Society for Developmental Biology
The meeting is January 30 in Utrecht.

January 18 – abstract submission deadline for the joint meeting of the British Societies for Cell and Developmental Biology
March 17-20 Warwick University
Early registration discount ends February 15.

January 31 – abstract submission deadline for the International joint meeting of the German Society for Cell Biology and the German Society for Developmental Biology
March 20-23 Heidelberg
Early registration discount ends February 15

February 1 – application deadline for the Woods Hole Embryology Course
(This is the course that produces the wonderful images that you’ve seen on the Node and on Development covers.)
June 1 – July 14 2013

Other deadlines:
The deadline to apply for the job of Community Manager for the Node is on January 20.

Less urgent, but worth noting:
Registration will soon* open for the 17th International Congress of Developmental Biology. This meeting is only held every four years, and this year it’s in Cancun, so you won’t want to miss this!

(* I first wrote “January 21st”, but had it mixed up with the JSDB meeting )

(1 votes)

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Abcam is a leading web based business supplying research tools to life scientists worldwide. Our head office is in Cambridge (UK), we also have offices in Bristol (UK), Cambridge, Eugene and San Francisco, (USA), Tokyo (Japan), Hong Kong and Hangzhou (China).

A position has become available to develop the product portfolio in the Epigenetics and Nuclear Signalling research area.

You will be part of a larger team responsible for identifying and prioritising targets for antibody production at Abcam. You will be key in ensuring the antibodies produced receive the highest level of validation and data using both internal and external resources. The role will focus on investigating key topics within the field of Epigenetics and Nuclear Siganalling and driving antibody production to meet customer needs. The ideal candidate will be flexible, work well in a team, be comfortable working to deadlines, prioritising different tasks and have good attention to details. Excellent communication skills are essential. You will have contacts within the scientific community and be confident networking to establish new links. Research experience in the field of Epigenetics, Chromatin or Nuclear Signalling is essential.

This position will provide an exciting opportunity for a motivated individual with a PhD or significant research experience who is looking to make the step into a more commercial environment. All relevant training will be provided.

Key Responsibilities:
i) Develop a strategy to identify new targets for antibody production in the field of Epigenetics and Nuclear Signalling. Prioritise production of the most commercially and scientifically valuable antibodies
ii) Post-production validation and characterization of existing antibodies using both internal and external resources.
iii) Networking with the scientific community to identify unmet needs and new product opportunities for Abcam
iv) Providing scientific guidance and input to troubleshoot production or QC issues for key products, working closely with our laboratory and other members of the team
v) Identify current and upcoming scientific topics in order to provide data/information to the Marketing department, including but not limited to, topics for marketing literature, scientific meetings, top selling products.

Our culture is one that empowers individuals, with responsibility given at an early stage. We place great emphasis on knowledge and experience. The working environment is fun and fast-paced, with everybody working together as a team to deliver great service and the best products to our customers. In addition to competitive salaries we can offer an attractive flexible benefits package which includes a profit-share scheme and share options.

To apply, or for more information please follow this link and submit your CV and cover letter: http://hire.jobvite.com/j/?cj=ozd0Wfws&s=The_node

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Here at Development, we’re delighted to welcome François Guillemot to the team of academic editors. François will be replacing Alexandra Joyner, who is soon to step down as our neurodevelopment expert. François heads up the Division of Molecular Neurobiology at the National Institute for Medical Research in London, and his research focuses on the regulation of neurogenesis in the mouse forebrain.

I’d like to take this opportunity to thank Alex for her dedication to and enthusiasm for the journal over the last five years, and to welcome François on board. Given that they used to work together, it should be a seamless transition!

(3 votes)

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A Postdoctoral Fellow position is available in my laboratory.

The overall goal of our laboratory is to understand the cellular and molecular basis of vertebrate organogenesis. Our primary focus is on the elucidation of the mechanisms that govern fate decision and cellular plasticity within the endoderm, for example between pancreas and liver. Toward this aim we perform comparative studies using both amphibian and mammalian model systems, including mouse models and embryonic stem cells.

This position seeks a highly motivated individual with a strong interest in developmental biology. Successful candidate should have a recent Ph.D. or M.D./Ph.D. degree, with strong expertise in one or more of the following areas: genetics, cell and molecular biology, and biochemistry. Prior experience with mouse models and ES cells is a plus. The applicant should be independent and collaborative to be part of a young team and be available for an interview.

Please send your CV, a brief description of your research, and contact information of three references to:

FRANCESCA M. SPAGNOLI, MD PhD

Laboratory of Molecular and Cellular Basis of Embryonic Development
Max Delbrück Center for Molecular Medicine
Robert-Rössle-Str. 10
13125 Berlin
Germany
francesca.spagnoli [a] mdc-berlin.de

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Why did you incubate that sample for 16 hours? Because you wanted to go home for the day – but that much detail is not in your paper! Last night, a few scientists on Twitter started sharing their “overly honest methods”, and today the #overlyhonestmethods hashtag exploded with lots of funny and true stories about scientific experimentation. There are thousands of tweets, still coming in, so I can’t show you all of them, but here is a selection of some of my favourites:

(9 votes)

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Here are the research highlights from the current issue of Development:

Directed differentiation: Nodal steps forward

The directed differentiation of pluripotent stem cells into endodermal derivatives, including insulin-producing pancreatic β cells, has considerable clinical promise in cell replacement therapies. The first step in this process is the conversion of pluripotent stem cells into definitive endoderm (DE). Here (p. 675), Douglas Melton and colleagues investigate the endodermal populations generated from mouse embryonic stem cells treated with Nodal (which is required for in vivo development of DE) or Activin A (which is thought to mimic Nodal activity). These TGFβ family members use the same signalling pathways but, although the researchers show that Nodal- and Activin-derived DE cells have similar gene expression patterns, Nodal-derived endoderm contributes much more efficiently to embryonic endoderm upon transplantation into the gut endoderm of mouse embryos. Importantly, this functional difference between Nodal- and Activin-derived endoderm extends to the subsequent development of pancreatic progenitors in vitro and maturation into insulin/c-peptide-expressing cells in vivo. These data provide a firm basis for the derivation of insulin-producing cells for disease modelling and cell therapy.

Unpaired Sox17 models biliary atresia

Congenital biliary atresia is an incurable disease of newborn infants that is characterised by deformation of the gallbladder and biliary duct system. Yoshiakira Kanai and co-workers now report (p. 639) that haploinsufficiency of Sox17 in C57BL/6 background mice provides a genetic model for this poorly understood condition. The researchers show that SOX17, a transcription factor that is required for definitive endoderm development in various vertebrate species, is expressed at the distal edge of the gallbladder primordium during gallbladder and bile duct development. In Sox17^+/− C57BL/6 embryos, cell-autonomous defects in the proliferation and maintenance of the gallbladder/bile duct epithelia lead to epithelial cell detachment from the luminal wall, bile duct atresia (blockage), bile leakage and inflammation in the bile ducts and liver at late foetal stages. These results suggest that SOX17 has a dose-dependent function in the morphogenesis and maturation of gallbladder and bile duct epithelia during late organogenesis and provide new insights into the pathogenesis of congenital biliary atresia.

Embryonic DNA methylation without Dnmt3L

During embryogenesis and gametogenesis, the DNA methyltransferases Dnmt3A and Dnmt3B establish the genome-wide methylation patterns that are essential for mammalian development and reproduction. The catalytically inert Dnmt3-like (Dnmt3L) is known to regulate de novo methylation in the germline but does it function in the early embryo? Déborah Bourc’his and colleagues have been investigating this question and, on p. 562, they report that, although mouse embryos initially contain a maternal store of Dnmt3L, the protein is rapidly degraded. The researchers show that zygotic Dnmt3L deficiency slows down the rate of de novo methylation in the embryo by affecting methylation density at some, but not all, genomic sequences. Importantly, however, Dnmt3L is not strictly required for de novo methylation in the embryo because methylation patterns are eventually established in its absence, possibly through upregulation of Dnmt3A. De novo methylation can therefore be achieved in vivo without Dnmt3L, which suggests that early mouse embryos are more plastic than the germline in terms of how they acquire de novo methylation patterns.

Mending a broken heart

Human hearts do not regenerate after a heart attack because adult mammalian cardiomyocytes proliferate poorly in response to injury. By contrast, zebrafish regenerate heart muscle after trauma by inducing cardiomyocyte proliferation. Studies of zebrafish heart regeneration might, therefore, identify ways to repair damaged human hearts. Here (p. 660), Wen-Yee Choi and co-workers develop a surrogate model for zebrafish heart regeneration that uses fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology to visualise cardiomyocyte proliferation in live zebrafish embryos. The researchers generate transgenic lines in which heart-specific promoters drive the expression of G₁ and S/G₂/M FUCCI probes and use these lines to identify several small molecules that alter cardiomyocyte proliferation during heart development. These molecules act via the Hedgehog, IGF or TGFβ signalling pathways, they report. Moreover, the researchers show, the same pathways are activated in regenerating zebrafish cardiomyocytes, and their pharmacological manipulation alters cardiomyocyte proliferation during adult heart regeneration. Future use of this new screening system may identify molecules with the potential to improve human heart regeneration.

Eyeing up proneural bHLH factors

During retinal development, seven retinal cell types are specified from a common pool of retina progenitor cells (RPCs). Several proneural basic helix-loop-helix (bHLH) transcriptional regulators, including Atoh7 and Neurod1, direct the intrinsic programming of RPCs but how do individual bHLH factors influence RPC fate? On p. 541, William Klein and colleagues ask whether replacing one bHLH gene with another redirects the fate of RPCs. Previously, the researchers showed that Neurod1 can replace the function of Atoh7 in specifying retinal ganglion cells (RGCs), which suggests that Atoh7-expressing RPCs are pre-programmed to produce RGCs. Now, they report that insertion of Atoh7 into the Neurod1 locus reprogrammes Neurod1-expressing RPCs, which normally produce amacrine and photoreceptor cells, into RGCs. Thus, Atoh7 acts dominantly to specify an RGC fate. The researchers also identify an Atoh7-dependent enhancer within its target gene Nrxn3 that is used by Atoh7 but not by Neurod1 in the developing retina. Together, these results provide new insights into the specification of retinal cells by proneural bHLH factors.

Body elongation goes with the flow

The tailbud is the posterior leading edge of the growing vertebrate embryo. Now, by measuring the three-dimensional cell flow field of the zebrafish tailbud, Scott Holley and co-workers reveal a posterior flow within the tailbud that reflects ordered collective cell migration (p. 573). They identify a transition in tissue fluidity at the tailbud tip where there is a decrease in the coherence of the cell flow but no alterations of cell velocities. Inhibition of Wnt or Fgf signalling reduces the coherence of the flow, but affects trunk and tail extension differently. By using computer simulations to interpret these complex phenotypes, the researchers show that a decrease in the coherence of the flow combined with a normal flow rate leads to a ‘traffic jam’ in the posterior tailbud and a severely contorted trunk, whereas decreases in both coherence and flow rate merely ‘kink’ the tip of the tail. Thus, the balance between flow rate and the coherence of collective migration within the tailbud steers zebrafish body elongation.

PLUS…

Transcriptional repressors: multifaceted regulators of gene expression

Although classic repressors undoubtedly silence transcription, genome-wide studies show that many repressors are associated with actively transcribed loci. Reynolds, O’Shaughnessy and Hendrich review this evidence and propose that the modulation of gene expression by co-repressor complexes provides transcriptional fine-tuning that drives development. See the Review on p. 505

Establishing and maintaining gene expression patterns: insights from sensory receptor patterning

Rister, Desplan and Vasiliauskas review the mechanisms that generate and maintain sensory receptor expression patterns and compare them to those that control sensory receptor expression patterns in the mouse retina and in the mouse and fly olfactory systems. See the Primer article on p. 493

Click here to see other articles in the ‘Development: The Big Picture’ series.

Radial glia – from boring cables to stem cell stars

As part of the ‘Development Classics’ series, Malatesta and Gotz look back at their 2000 Development paper, in which they showed that radial glial cells act as neural stem and progenitor cells in development – a discovery that has led to a change in the concept of neural stem cells in the adult brain. See the Spotlight on p. 483

A germline-centric view of cell fate commitment, reprogramming and immortality

At the recent EMBO/EMBL symposium ‘Germline – Immortality through Totipotency’, researchers discussed the mechanisms that establish and control totipotency, with an eye towards the mechanisms that may endow germ cells with the ability to propagate totipotency across generations. See the Meeting Report by Torres-Padilla and Ciosk on p. 487

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A postdoctoral position is available in the laboratory of Dr. Sophie Astrof to study roles of cell-extracellular matrix interactions in cardiovascular development and disease using mouse model system. The research will involve investigation of the role of extracellular matrix in orchestrating signaling/communication between various progenitor cell populations during morphogenesis of the aortic arch arteries.  In our lab, we use genetics, conditional mutagenesis, and transgenic approaches to explore roles of tissue microenvironment during organogenesis and disease. Experience with genetic manipulation, embryology and cell biology is desirable.  My laboratory is a part of the Center for Translational Medicine at Jefferson Medical College (http://www.tju.edu/jmc/medicine/translational_medicine/faculty/astrof.cfm?detail=0) located in the heart of Philadelphia. To apply, send a letter of interest, CV and names and contact information of three references to sophie.astrof@gmail.com

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