Nathan M. Hunkapiller and Susan J. Fisher

To accompany our research article in issue 138 (14) of Development, “A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia,” we have been asked by the Node to provide a broader context to the work and to explore the possible medical implications of our findings.   http://dev.biologists.org/lookup/doi/10.1242/dev.066589

This work stems from our group’s interest in identifying the molecular and physiological mechanisms that govern placental function in normal human pregnancy and in pregnancy complications. Through their aggressive invasion of the uterine wall and resident blood vessels, human cytotrophoblasts (CTBs) anchor the placenta to the uterus and redirect maternal blood to the developing fetus. Interestingly, CTBs exhibit an arterial tropism, which suggests that these cells have the machinery to specifically recognize these vessels or are programmed to invade with an arterial bias. A study by a previous graduate student in our lab (Red-Horse et al., 2005) showed that CTBs achieve this specificity, in part, by co-opting mechanisms involved in neuronal guidance and vascular patterning. Specifically, as CTBs differentiate and invade the uterine wall, they upregulate expression of EphrinB2, which promotes their migration away from the placenta and toward maternal arteries in the uterine wall. As this molecular system is also utilized in developing vascular beds to segregate arteries and veins, we theorized that CTB invasion might be programmed by other upstream factors that govern vascular patterning, namely the Notch signaling family.

To test this hypothesis, we first used an immunolocalization approach to profile CTB expression of Notch family members in tissue sections of the human maternal-fetal interface. The results revealed extensive modulation of both receptors and ligands as the cells differentiated and invaded the uterine wall and resident arterioles. Functional blockade of Notch signaling reduced CTB invasion and expression of the arterial vascular marker, EphrinB2, which is normally upregulated as the cells invade maternal vessels. Second, we used a mouse model to further explore Notch function in this context. Employing a transgenic Notch reporter strain, we confirmed that Notch activity was highest in artery-associated trophoblasts. Deletion of the only receptor upregulated during trophoblast invasion (Notch2) highlighted the central importance of this signaling pathway in coordinating increases in utero-placental blood flow during pregnancy; trophoblast invasion of maternal arterioles failed, the blood canals that supply the placenta were smaller, and placental perfusion was decreased. The end result was litter-wide lethality proportional to the number of mutant offspring. Lastly, we asked whether defects in CTB expression of Notch family members were evident in preeclampsia, a pregnancy complication that is causally related to failed vascular transformation. An absence of endovascular CTB expression of the Notch ligand, JAG1, was frequently observed, suggesting that failures in Notch signaling are an important part of the pathogenesis of this condition.

Although development of the human placenta has many different components, we know that the tumor-like process in which CTBs invade the uterine vessels, which incorporates this transient organ into the uterine circulation, is a particularly key step. Why? Failures in this process lead to the dangerous pregnancy complication, pre-eclampsia (maternal high blood pressure, proteinuria and edema; impaired fetal growth). Our results suggest a molecular basis for abnormal placentation in this pregnancy complication and give us new clues about the pathways that are involved. These findings add weight to the theory that pre-eclampsia is associated with a failure of the mechanisms, borrowed from the vasculature, that integrate placental trophoblasts with uterine blood vessels.

Hunkapiller, N., Gasperowicz, M., Kapidzic, M., Plaks, V., Maltepe, E., Kitajewski, J., Cross, J., & Fisher, S. (2011). A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia Development, 138 (14), 2987-2998 DOI: 10.1242/dev.066589

(4 votes)

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Tomorrow is the Node’s first birthday, which means we’ve been online for a year now. We’ve taken a look at the archive of the past year as a reminder of what we’ve featured on the site. Please join us on this trip down memory lane.

A quick look back at the Node’s first year:

June 2010 – We launched the Node, Shelley Edmunds showed us how to make an embryo out of modelling clay, Benoit Bruneau pondered the overlap between stem cells and developmental biology.

July 2010 – We had an official launch party at the Gurdon Institute in Cambridge, we heard from students at the Woods Hole Embryology course and people discussed whether there are perhaps too many postdocs and PhD students.

August 2010 – Natascha Bushati pondered white peacocks at a lab retreat, we interviewed Jorge Cham of PhD comics, and American stem cell researchers worried about the future of their federal funding.

September 2010 – The team behind BioEYES explained how they use zebrafish in outreach projects, Kim Cooper introduced us to jerboas and Shreeharsha wrote about his research trip to Japan and how Japanese culture differs from India.

October 2010 – Erin Campbell’s first image feature appeared on the Node and she showed the beauty of fly ovarian cysts, Fer Cesares summarized the Company of Biologists workshop on Stochasticity, and Karen Yook took us on a tour of WormBase.

November 2010 – Heather Etchevers asks how people share PCR primers with their colleagues, Sivani Paskaradevan attended the Gairdner Award lectures in Toronto and Pablo Astudillo reviewed the LASDB meeting in Chile.

December 2010 – Bruno Vellutini showed a video he made of sea biscuit development, Pepperdine University students sang about Hox genes, and Christian Mosimann and Anita Abu-Daya took us behind the scenes of their papers on (respectively) a new tool for zebrafish research and frog limb development.

January 2011 – Linda Lin mused about the mobility of researchers, Erin Campbell started cross-posting to the EuroStemCell site, Janel Kopp elaborates on her paper about the role of duct cells in pancreatic regeneration, the NIH introduced a grant for people to skip their postdoc (but our poll showed that most of you wouldn’t apply for it), and stem cell pioneer Ernest McCulloch died at the age of 84.

February 2011 – The SFBD reached out to French researchers abroad, while the Dutch Society for Developmental Biologists relaunched and just had their first meeting, Nicole Husain shared how she moved from the lab to designing computer games about biology, and the Primitive Streak fashion exhibit went on tour.

March 2011 – We featured Ed Yong’s interactive timeline of iPSC research and interviewed some of the winners of the Wellcome Image Awards, the European Advocate General was critical of stem cell patents, and some labs in Japan were affected by a devastating earthquake and tsunami.

April 2011 – Khalil Cassimally attended a Melbourne rally against funding cuts for Australian biomedical research, Ken Hastings reports on a new tunicate database portal, and Jean-Pierre Saint-Jeannet gives the backstory about his research on mapping the cardiac neural crest in the frog’s heart.

May 2011 – Jonathan Lawson summarized the “Science – the bigger picture” session of the BSDB/BSCB meeting, David Page and Patricia Ann Jacobs were awarded the 2011 March of Dimes Prize, Raman Das and Nick van Hateren performed an RNAi screen in a whole vertrebrate, and Carlos Carmona-Fontaine compared neural crest cell migration to locust flight patterns.

June 2011 – Development featured the first cover selected by Node readers, several labs are looking for postdocs and PhD students and it’s the Node’s first birthday!

(3 votes)

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Here is part 3 of my report on the 2011 BSCB-BSDB Spring Conference this April in Canterbury. In the first part, I covered Mark Krasnow’s amazing opening lecture on lung development, and in part two I introduced this year’s awardees of the BSCB and BSDB honorary medals.

Here I’ll highlight some of the talks in which the researchers used mathematical or computational modelling to understand and predict the behaviour of their system – in modelling terms they “explored the model’s parameter space”. Modelling your favourite biological system is very popular these days, which might be one of the reasons why a well-attended lunchtime workshop on the topic took place at the meeting. Its main take-home message was that modelling usually takes a lot longer than one might imagine, and therefore one shouldn’t underestimate the need for stable long-term collaborations or having a modeller or programmer in the lab.

The talks involving modelling spanned an array of topics, an indication of the widespread implications of the discipline. The subjects ranged from Enrico Coen‘s (John Innes Center, Norwich, UK) beautiful analyses of growth rates and the establishment of polarity during Arabidopsis leaf development, through Yogi Jaeger‘s (CRG, Barcelona, Spain) and Thomas Gregor‘s (Princeton University, USA) models of fly embryonic development, to Kees Weijer‘s (University of Dundee, UK) computational models of chemotactic cell migration in Dictostylium development and chick gastrulation. Here I’ll focus on just two of the studies.

Marie-Anne Félix (Institut Jacques Monod, CNRS-Université Paris Diderot, Paris, France) presented her lab’s recent work on the effect of quantitative variation within the intercellular signalling network that underlies C. elegans vulval development. Using a computational model of this network they varied the parameters of the model, without altering the network’s architecture, and analysed the phenotypic outcomes. A large fraction of the solutions turned out to result in the wild type pattern of vulva cell specification. Previously, two competing models of vulva cell precursor induction – one morphogen-like, the other involving a sequence of direct cell-cell signalling events had been proposed. Examining the parameter sets generated by the computational analysis revealed that they corresponded to either one or the other, or a mixture of the two mechanisms. This suggested that the two experimentally proposed mechanisms can function independently or in concert via the same network topology with the relative contribution of the two mechanisms depending on the quantitative tuning of parameters. Finally, Marie-Anne showed that inter-species differences in vulval patterning can be achieved by quantitative modulations of the very same network.

Denis Headon‘s lab (The Roslin Institute, University of Edinburgh, UK) is interested in vertebrate skin field patterning: Regional differences in the skin’s periodic micropattern of hair or feather follicles constitute the skin’s macropattern. To tackle the molecular pathways underlying macropattern generation, they took advantage of the Naked neck mutant, a naturally occurring chick mutant with a bare neck and lower overall feather density. Having pinned down the insertion associated with the trait, they identified increased levels of BMP12/GDF7 as the cause of the naked neck phenotype. They found that neck skin is more sensitive to BMP than the rest of the body since it selectively produces retinoic acid, which amplifies the effect of elevated BMP. This results in the complete loss of neck feathers. To validate the hypothesis, Denis showed the results of a mathematical model of the reaction-diffusion system of inhibitors and activators known to produce the periodic micropattern of feathers. Testing whether varying inhibitor (BMP) sensitivities, might lead to the macropatterning phenomenon observed in the mutant confirmed that a sharp pattern boundary between neck and body could explain the differences in feather density between neck and body, both in the wild type and at different BMP signalling levels. The simulated and experimental patterns astonished me as they looked more like graphic design than biology – it’s definitely worth having a look!

With these talks, the meeting provided examples of how modern developmental biology is indeed alive and kicking. To include modelling in the analysis is clearly one of the effective directions the field is taking, and in my final post on the Canterbury meeting I’ll highlight one of the other fruitful directions – live imaging.

Hoyos E, Kim K, Milloz J, Barkoulas M, Pénigault JB, Munro E, & Félix MA (2011). Quantitative variation in autocrine signaling and pathway crosstalk in the Caenorhabditis vulval network. Current biology : CB, 21 (7), 527-38 PMID: 21458263

Mou C, Pitel F, Gourichon D, Vignoles F, Tzika A, Tato P, Yu L, Burt DW, Bed’hom B, Tixier-Boichard M, Painter KJ, & Headon DJ (2011). Cryptic patterning of avian skin confers a developmental facility for loss of neck feathering. PLoS biology, 9 (3) PMID: 21423653

(5 votes)

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The 3D spatial arrangement of DNA within the nucleus is tightly controlled and has great functional significance. Each chromosome has been shown to occupy a defined nuclear territory and the expression of genes is often closely linked to where they are located, with similar expression levels seen for genes with similar locations. It has also been shown that disrupting localisation affects gene regulation.

A new paper, in Genes & Development, has investigated the importance of spatial positioning in the inactivated X chromosome. The X chromosome is considerably larger than its alternative, the Y chromosome, as such males often have one copy of a gene (on the X, with no Y equivalent) whilst females have two. This disparity can cause difficulties in correct gene activity and so regulatory mechanisms are needed. In mammals, females prevent a doubling of X activity by shutting down the activity of one, generating an inactive X chromosome.

This research has shown that the gene silencing involved in X inactivation is connected to the spatial arrangement of the chromosome within the nucleus. For the active X, long stretches of DNA from different parts of the chromosome form many stable associations which are consistently maintained in different cells, with different interacting regions corresponding to active and inactive genes. However, Splinter et al. have shown that the inactive X chromosome is randomly packaged with a lack of consistent interactions.

Within the disordered inactive X conformation, the group were able to identify some genes with spatial architecture suggestive of active gene expression, these ‘escapees’ form long-range contacts with each other, similar to those seen for active genes on the active X chromosome, and other regions of the genome. These observations have effectively doubled the number of ‘escapees’ which now require further investigation.

Of the active genes identified, Xist, a non-protein coding RNA, which is known to be involved in X inactivation, is of particular interest. It has now been shown that Xist may function by affecting chromosome topology. Loss of Xist correlated strongly with a switch to the ordered, active X conformation but did not cause gene reactivation or alterations to the histone code.

Study of spatial arrangements within the nucleus has added a whole new dimension to our understanding of gene regulation. The inactive X chromosome is a particularly striking example of gene silencing, but can be a very useful tool in understanding the intricacies of these regulatory mechanisms and their impact on our lives.

Splinter E, de Wit E, Nora EP, Klous P, van de Werken HJ, Zhu Y, Kaaij LJ, van Ijcken W, Gribnau J, Heard E, & de Laat W (2011). The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. Genes & development PMID: 21690198

(3 votes)

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Congratulations to Meii Chung of UT Austin, whose image of a Cerebratulus pilidium larva won first place in the latest voting round to choose a cover for Development from images taken by students of the 2010 Woods Hole Embryology course.

Pilidium larva of the Nermertean, Cerebratulus lacteus. Acetylated tubulin (green), serotonin (red), nuclei (blue, DAPI).

The runners-up in this voting round were Joshua Clanton of Vanderbilt University (fly embryo nervous system), Valeria Merico of the University of Pavia (planaria), and Elise Delagnes and Hannah Rollins of UC Berkeley (fly embryo staining showing tropomyosin/Ubx/Spalt).

Thanks to everyone for participating and voting!

The next round of images will be up on July 11, and in the meantime you’ll be able to read posts from students currently taking the Woods Hole Embryology course.

(4 votes)

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The Cell: An Image Library is honored to be named a finalist in the website Labby Awards. Please help us win this award and vote for us at the site below. Please be patient if the site does not load right away and apologies for cross posting. Please tell your friends to vote for us as well.
http://the-scientist.com/2011/06/15/2011-labby-website-finalists/

(2 votes)

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The laboratory of Berta Alsina at UPF-Parc de Recerca Biomèdica de Barcelona is seeking a highly motivated student for a PhD in Inner Ear Sensory Development and Regeneration.

This PhD project will address the question on how FGF and Retinoic Acid signals regulate the development and regeneration of sensory cells and how extrinsic signals are integrated at a molecular level. We use the zebrafish as model system to address these questions. You will be combining functional experiments through transgenic fish lines, in vivo imaging of progenitors and studies of regulatory regions by computational and ChIP experiments. The project provides multidisciplinary training using state-of-the-art techniques and you will therefore be well placed for a future career in biomedical sciences.

The Department of Experimental Life Sciences at Universitat Pompeu Fabra (http://www.upf.edu/cexs/) is part a leading biomedical research center with an excellent international projection. The PRBB (www.prbb.org) , located in front of the sea and highly international, will provide you with a young, dynamic and interacting atmosphere to ensure you opportunities to discuss and learn from experts in diverse fields.

Applicants should have a BSc in biomedical science (or equivalent) amd a master degree with strong academic record to apply to competitive PhD fellowships. Applicants should be highly motivated in the field of stem cell, developmental biology and regeneration and be familiar with developmental biology techniques. Basic knowledge of programming or zebrafish manipulation will be strongly encouraged.

The position will be available from september 2011 for three years. Funding is available for the first year.

If interested please send your application (including CV and BSc academic record) by e-mail to:

Berta Alsina, PhD

Laboratory Developmental Biology

Universitat Pompeu Fabra-PRBB

Dr. Aiguader 88, 08003 Barcelona

Phone: 34-93-3160837

berta-alsina@upf.edu

http://www.upf.edu/devbiol/projectes/Alsina_lab.html

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The fifth international EMT (epithelial-to-mesenchymal transition) meeting will be held this year from Oct 10 to Oct 13 in the beautiful city state of Singapore.  The meeting is co-organized by Jean Paul Thiery and Erik Thompson. It will cover recent development in the EMT field, ranging from basic molecular and developmental mechanisms to translational research (cancer, stem cell and clinical applications).

EMT/MET is a fairly common phenomenon in animal development. For those of you working on basic developmental biology, but interested in having a wider perspective of your research that funding agencies love to hear, this meeting will be a great opportunity.

Conference Website: www.emtmeeting.org

Registration: Early Bird Registration closes on 30 June 2011. Regular registration opens from 1 July.

(3 votes)

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I’m currently in Toronto for the annual meeting of the International Society for Stem Cell Research (ISSCR), and you can expect to find updates about the meeting at various places. Of course we’ll cover it here on the Node itself, but we’re also using Twitter to share and follow news from the meeting.

The ISSCR meeting has a wonderful media policy, where the embargoes end at the start of each talk, so you can write about them as they happen, and the meeting organisers actively encourage blogging and tweeting. There is an official “Twitter hashtag” for the meeting which you can use to follow along with updates from people who are at the meeting. (That even works if you don’t use Twitter yourself, so don’t worry if you’re not an active social media user.)

This is a link to a list of tweets from people writing about the ISSCR meeting:
all recent tweets tagged #ISSCR2011. (Newest ones are on top.)

I will be using both the Node’s and Development‘s Twitter accounts to post updates as appropriate. You can find those here:
the Node on Twitter
Development on Twitter

And finally, for the official word on the meeting, the ISSCR has its own Twitter account.

(2 votes)

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POSTDOCTORAL POSITIONS are available to study the cellular and molecular mechanisms controlling the development of the lymphatic vasculature and its functional roles in normal and pathological conditions including obesity and cancer using available mouse models. Highly motivated individuals who recently obtained a PhD or MD degree and have a strong background in molecular, cancer 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, Member
• Department of Genetics
• St. Jude Children’s Research Hospital
• 332 N. Lauderdale, Memphis, TN 38105
• E-mail: guillermo.oliver@stjude.org
• http://www.stjude.org/oliver

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