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Embryonic stem cells – keeping a clean slate

Posted by , on 15 August 2011


Do your ears perk up when you hear about embryonic stem cells?  We all have heard and/or participated in the controversy surrounding the use of them, yet there is no debate over their biological importance and medical potential.  A paper in Journal of Cell Science describes the newly-indentified role for Banf1 in ESC self-renewal.

Embryonic stem cells (ESCs) maintain their pluripotent state through a complicated process called self-renewal.  Self-renewal of ESCs is dependent on three main regulators—Sox2, Oct4, and Nanog.  Recently, Cox and colleagues conducted a proteomic screen to find proteins that associate with Sox2, and identified the DNA-binding protein Banf1.  Banf1 was already known to play important roles in worm and fly development, yet its role in mammalian development was unclear.  Cox and colleagues found that Banf1 is required for mouse and human ESC self-renewal.  The use of RNAi to reduce Banf1 levels led to differentiation of mouse ESCs into mesoderm and trophectoderm cell lineages.  As seen in the images above, Banf1 knockdown (middle and right columns) caused cell to no longer have the characteristic pluripotent ESC morphology (left column).  Banf1-reduced cells were more flattened, had more membrane processes, and showed less staining for the pluripotent stem cell marker alkaline phosphatase (red, bottom row).  When investigating the specific mechanism likely affected by Banf1 knockdown, Cox and colleagues found that cell cycle distribution was altered in mouse and human ESCs – Banf1 knockdown resulted in a higher portion of cells in G2-M phase, and fewer cells in S-phase.

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

ResearchBlogging.orgCox JL, Mallanna SK, Ormsbee BD, Desler M, Wiebe MS, & Rizzino A (2011). Banf1 is required to maintain the self-renewal of both mouse and human embryonic stem cells. Journal of cell science, 124 (Pt 15), 2654-65 PMID: 21750191

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The Wonder of Stem Cells

Posted by , on 12 August 2011

At the ISSCR meeting in Toronto in June I noticed this display at the top of the escalators:

These fabrics with patterns related to stem cells are part of an ongoing exhibition at Toronto’s Ontario Science Centre (OSC). In collaboration with the Stem Cell Network, the “Super Cells: The Wonder of Stem Cells” exhibit displays stem cell-inspired work by students from art schools across the city of Toronto.

At the museum itself, this is one of the works on display:

Stem Cell Fashion
(Image by Ricardipus on Flickr, used with permission. Click image for more info.)

The fashion aspect of the exhibit reminds me a bit of Primitive Streak, but Super Cells covers other art forms as well.

From the press release:

“This year marks the 50th anniversary of the discovery of stem cells by Canadian scientists Drs. James Till and Ernest McCulloch. “Till and McCulloch’s discovery in 1961 was unparalleled at the time and their findings continue to influence the field of stem cell research to this day,” said Drew Lyall, Executive Director of the Stem Cell Network. “This exhibition is a fitting tribute to their work, which took place here in Toronto.” “

In addition to the exhibit, the museum also organised Skype chats with stem cell researchers during the ISSCR meeting. Visitors to the science centre could ask delegates of the ISSCR meeting about their research via Skype. I didn’t get a chance to see this at the conference (so I don’t know who was interviewed), but the chats will hopefully be posted on the science centre’s YouTube channel.

Super Cells is at the Ontario Science Centre until October 2nd, 2011. If you’re in Toronto before then, take a look. The rest of the museum is really great as well!

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Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development

Posted by , on 9 August 2011

Since I was an undergraduate student at the Veterinary School in Milan, and throughout the rest of my scientific career, I have been fascinated with the complexities of mammalian preimplantation development. That’s why the publication of our recent paper “Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development” feels like the natural conclusion of a long journey that started with buckets of cow ovaries in Italy, and ended with a collective effort shared by our team in the Stem Cell Bank at the Center for Regenerative Medicine in Barcelona (CMR[B]), under the direction of Drs Izpisua Belmonte and Veiga.

In just hours, the newly formed mammalian embryo terminates the program of the two gametes that formed it, escapes apoptosis, remodels its chromatin to a functional state, starts dividing, and turns on its genome while using up the reserves of protein and RNA inherited from mum (and dad, a little). This last process, termed embryonic genome activation (EGA), represents one of the first signs of “independent life” of a new individual.

As much as the researchers at the CMR[B] are used to manipulating embryos and work with tiny amount of material, studying preimplantation processes in general, and EGA in particular, is a great challenge in our species, as embryos are very scarce, heterogeneous in quality, and RNA amplification methods almost invariably introduce a very significant bias in downstream data quality. An incredible opportunity to look into details of this process came as the CMR[B] established a collaboration with Herbert Auer of the University of Barcelona. His facility just recently validated a method to amplify very small amount of RNA without bias, and we proceeded to apply this “pico-profiling” to a very detailed time course of single human embryos.

Among the many complex interactions that our study has unveiled, one certainly stands out: the human embryo starts EGA one full day before we thought since seminal works were published more than 30 years ago (Braude et al, 1988). Using a combination of extremely reliable transcriptional profiling and de novo transcription inhibition by amanitin treatment, we have been able to show that the human embryo transcribes from its own genome as early as the 2-cell stage (about 30hr after fertilization).

In order to make our data genome-wide expression data easily available to the scientific community at large we have prepared a free online database, HuMER (Human Embryo Resource; http://intranet.cmrb.eu/Human_embryos/home.html). It is our hope and desire that this resource would help us improve our ability to draw interdisciplinary connections between biological events and, in the process, increase our understanding of preimplantation development.

Written by first author of the paper, Dr. Rita Vassena.

ResearchBlogging.orgVassena, R., Boue, S., Gonzalez-Roca, E., Aran, B., Auer, H., Veiga, A., & Belmonte, J. (2011). Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development Development, 138 (17), 3699-3709 DOI: 10.1242/dev.064741

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In Development this week (Vol. 138, Issue 17)

Posted by , on 9 August 2011

Here are the highlights from the current issue of Development:

Human embryos make an early transcriptional start

Human preimplantation development is a highly dynamic process that lasts about 6 days. During this time, the embryo must complete a complex program that includes activation of embryonic genome transcription and initiation of the pluripotency program. Here, Juan Carlos Izpisua Belmonte and co-workers use pico-profiling (an accurate transcriptome amplification method) to reveal the timing of sequential waves of transcriptional activation in single human oocytes and embryos (see p. 3699). The researchers (who have developed HumER, a free, searchable database of their gene expression data) report that initiation of transcriptional activity in human embryos starts at the 2-cell stage rather than at the 4- to 8-cell stage as previously reported. They also identify distinct patterns of activation of pluripotency-associated genes and show that many of these genes are expressed around the time of embryonic genome activation. These results link human embryonic genome activation with the initiation of the pluripotency program and pave the way for the identification of factors to improve epigenetic somatic cell reprogramming.

See the post written by the first author of this paper for more information

Worming into organ regeneration

Planarian flatworms have amazing regenerative abilities. Tissue fragments from almost anywhere in their anatomically complex bodies can regenerate into complete, perfectly proportioned animals, a feat that makes planarians ideal for the study of regenerative organogenesis. Now, on p. 3769, Alejandro Sánchez Alvarado and colleagues provide the first detailed description of the excretory system of Schmidtea mediterranea, which consists of internal protonephridial tubules composed of specialised epithelial cells. Using α-tubulin antibodies to stain cilia in the planarian’s excretory system and screens of gene expression patterns in whole mounts, the researchers show that protonephridial tubules form a complex branching structure that has a stereotyped succession of cell types along its length. Organ regeneration originates from a precursor structure that undergoes extensive branching morphogenesis, they report. Moreover, in an RNAi screen of signalling molecules, they identify EGF signalling as a crucial regulator of branching morphogenesis. Overall, these results establish the planarian protonephridia as a model system in which to study the regeneration and evolution of epithelial organs.

Axons lead, lymphatics follow

Given the similar anatomies of vertebrate nerves, blood vessels and lymphatics, it is not surprising that guidance cues such as the netrins, which were discovered as molecules involved in axon pathfinding, also guide vessels. But do nerves and vessels share patterning mechanisms or do axons provide guidance for vessels? The laboratories of Dean Li, Chi-Bin Chien and Brant Weinstein now report that zebrafish motoneurons are essential for vascular pathfinding (see p. 3847). Netrin 1a is required for the development of the parachordal chain (PAC), a string of endothelial cells that are precursors of the main zebrafish lymphatic vessel. Here, the researchers identify muscle pioneers at the horizontal myoseptum (HMS) as the source of Netrin 1a for PAC formation. netrin 1a and dcc (which encodes the Netrin receptor) are required for the sprouting of the rostral primary axons and neighbouring axons along the HMS, they report, and genetic removal or laser ablation of these motoneurons prevents PAC formation. Together, these results reveal a direct requirement for axons in vascular guidance.

Satellite cells: stem cells for regenerating muscle?

Adult vertebrate skeletal muscle has a remarkable capacity for regeneration after injury and for hypertrophy and regrowth after atrophy. In 1961, Alexander Mauro suggested that satellite cells, which lie between the sarcolemma and basement membrane of myofibres, could be adult skeletal muscle stem cells. Subsequent cell transplantation and lineage-tracing studies have shown that satellite cells, which express the Pax7 transcription factor, can repair damaged muscle tissue, but are these cells essential for muscle regeneration and other aspects of muscle adaptability? In this issue, four papers investigate this long-standing question.

On p. 3639, Chen-Ming Fan and colleagues report that genetic ablation of Pax7+ cells in mice completely blocks regenerative myogenesis after cardiotoxin-induced muscle injury and after transplantation of ablated muscle into a normal muscle bed. Because Pax7 is specifically expressed in satellite cells, the researchers conclude that satellite cells are essential for acute injury-induced muscle regeneration but note that other stem cells might be involved in muscle regeneration in other pathological conditions.

Anne Galy, Shahragim Tajbakhsh and colleagues reach a similar conclusion on p. 3647. They report that local depletion of satellite cells in a different mouse model leads to marked loss of muscle tissue and failure to regenerate skeletal muscle after myotoxin- or exercise-induced muscle injury. Other endogenous cell types do not compensate for the loss of Pax7+ cells, they report, but muscle regeneration can be rescued by transplantation of adult Pax7+ satellite cells alone, which suggests that Pax7+ cells are the only endogenous adult muscle stem cells that act autonomously.

On p. 3625, Gabrielle Kardon and colleagues confirm the essential role of satellite cells in muscle regeneration in yet another mouse model. They show that satellite cell ablation results in complete loss of regenerated muscle, misregulation of fibroblasts and a large increase in connective tissue after injury. In addition, they report that ablation of muscle connective tissue (MCT) fibroblasts leads to premature satellite cell differentiation, satellite cell depletion and smaller regenerated myofibres after injury. Thus, they conclude, MCT fibroblasts are a vital component of the satellite cell niche.

Finally, on p. 3657, Charlotte Peterson and colleagues investigate satellite cell involvement in muscle hypertrophy. By removing the gastrocnemius and soleus muscles in the lower limb of mice, the researchers expose the plantaris muscle to mechanical overload, which induces muscle hypertrophy. After two weeks of overload, muscles genetically depleted of satellite cells show the same increase in muscle mass and similar hypertrophic fibre cross-sectional areas as non-depleted muscles but reduced new fibre formation and fibre regeneration. Thus, muscle fibres can mount a robust hypertrophic response to mechanical overload that is not dependent on satellite cells.

Together, these studies suggest that satellite cells could be a source of stem cells for the treatment of muscular dystrophies but also highlight the potential importance of fibroblasts in such therapies. Importantly, the finding that muscle regeneration and hypertrophy are distinct processes suggests that muscle growth-promoting exercise regimens should aim to minimise muscle damage and maximise intracellular anabolic processes, particularly in populations such as the elderly where satellite activity is compromised.

Plus…

Notch signaling: simplicity in design, versatility in function.

The evolutionarily conserved Notch signalling pathway operates in numerous cell types and at various developmental stages. Here, Andersson, Sandberg and Lendhal review recent insights into how versatility in Notch signalling output is generated and modulated.

See the Review article on p.3593

Evolution of nervous system patterning: insights from sea urchin development

Recent studies have elucidated the mechanisms that pattern the nervous system of sea urchin embryos. Angerer and colleagues review these conserved nervous system patterning signals and consider how the relationships between them might have changed during evolution.

See the Review article on p. 3613

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Wellcome Trust Conference on Mouse Molecular Genetics

Posted by , on 4 August 2011

For the past 24 years, the Mouse Molecular Genetics meeting has been a leading forum for researchers who apply the methods of genetics and genomics to fundamental problems in mammalian biology, including stem cell biology, early development, and models of human disease. In particular, the meeting showcases the latest technical developments in genetics and engineering of the mouse genome, and this year will feature a session devoted to imaging. The Mouse Molecular Genetics meeting assembles leaders in the field to present unpublished research findings, encourages junior investigators to participate in oral and poster presentations, and provides a stimulating environment for the exchange of ideas and information.

Sessions:
Epigenetics
Genetics and Genomics
Imaging
Models of Human Disease
Organogenesis
Patterning
Stem Cells and Germ Cells
Technology

Scientific Programme Committee:
Allan Bradley, Wellcome Trust Sanger Institute, UK
Kat Hadjantonakis, Sloan-Kettering Institute, USA
Haruhiko Koseki, RIKEN Research Center for Allergy and Immunology, Japan
Michael Shen, Columbia University Medical Center, USA

Keynote speakers:
Kathryn Anderson, Sloan Kettering Institute, USA
William Skarnes, Wellcome Trust Sanger Institute, UK

Speakers include:
David Adams, Wellcome Trust Sanger Institute, UK
Shinichi Aizawa, RIKEN CDB, Japan
Phil Avner, Institut Pasteur, France
Yann Barrandon, EPFL, Switzerland
David Beier, Harvard Medical School, USA
Richard Behringer, MD Anderson Cancer Center, USA
Shuomo Bhattacharya, University of Oxford, UK
Neal Copeland, Institute of Molecular and Cell Biology, Singapore
Xiaoxia Cui, Sigma-Aldrich Corp, USA
Elizabeth Fisher, UCL , UK
Scott Fraser, Beckman Institute, USA
Matthias Merkenschlager, MRC Clinical Sciences Centre, UK
Olivier Pourquie, Institute of Genetics and Molecular and Cellular Biology, France
James Sharpe, Centre for Genomic Regulation, Spain
Ludovic Vallier, Cambridge University, UK
Magda Zernicka-Goetz, The Gurdon Institute, UK

Conference Programme Information:
The conference will start on Tuesday, 20 September with registration at 14.00.
The conference will finish after lunch on Friday, 23 September 2011 at approximately 13.30.

https://registration.hinxton.wellcome.ac.uk/display_info.asp?id=258

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Adding events to the Node calendar

Posted by , on 4 August 2011

I’ve just added some 2012 conferences to the events calendar, and thought I’d give a quick reminder on how to add events here. If you have an account on the Node, you will have received these instructions when your account was approved. (And if you don’t have a Node account, you can get one here.)

When logged in, click “add/edit events” in the sidebar of the Node admin panel.

You’ll now get to the page where you can add an event. In the following picture, the numbers correspond to the list below:

1. Add name of event
2. Select both boxes (skip the first if there is no website)
3. Add start and end date of event
4. Add location
5. This is set to “conference” by default, but can be changed to “workshop” or “course”
6. Add website address

Don’t forget to save. Your event now appears on the events calendar!

If you want to share more detailed information about conferences (eg. if you’re organising one) you can write a post about it, but don’t forget to also add it to the calendar!

(Get these instructions as a pdf)

(NB – events that are not relevant to the developmental biology community, or commercial/sales events (such as product demos) will be removed from the calendar. If you’re not sure whether an event is suitable, you can contact us or leave a comment below.)

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International Developmental Biologists meeting 2012

Posted by , on 2 August 2011

ISDN2012 Neurodevelopment and Neurological diseases in Mumbai India.

http://www.isdn-conference.elsevier.com/

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An interview with Magdalena Götz

Posted by , on 1 August 2011

(This interview originally appeared in Development.)

Magdalena Götz is the Director of the Institute for Stem Cell Research at the Helmholtz Center and Professor at the Ludwig-Maximilians-University in Munich, Germany. Her developmental work in neurogenesis has identified radial glial cells as the source of neurons in the developing brain. Magdalena joined Development as Editor in 2010, and she agreed to be interviewed about her scientific inspirations and about finding a place for adult stem and progenitor cells within developmental biology.

When did you first become interested in science?

I have always loved biology, and in school I was truly inspired by my biology teacher. In our rather non-innovative school system, we had a young American biology teacher who made us actually think and do things, and I was simply fascinated.

What was your PhD about and how did it inform your subsequent career choices?

My PhD was on development of the cerebral cortex and investigated how specific cell types develop and form their specific connections. This work laid the basis for many research questions, which I continued to pursue into much later stages. For example, it led to the isolation of specific progenitor subtypes in order to understand stem cell and progenitor heterogeneity, and the molecular specification of these subtypes. The new questions that arose from my PhD project also determined how I chose my postdoc lab, and many of the basic questions from this time still keep us busy now.

Did you have a mentor or someone who inspired you in your early career?

After my inspiring biology teacher in school, my PhD supervisor, Jürgen Bolz, was also key in shaping my way. His readiness to discuss science at any time was certainly very important to further fuel my enthusiasm for understanding how the cerebral cortex develops. My interest in developmental biology was originally inspired by a course at the Max-Planck Institute for Developmental Biology in Tübingen and by the fascinating questions of axon growth and regeneration studied by Friedrich Bonhoeffer and Claudia Stürmer.

Typically, I have always been inspired by people we call `Querdenker’ in German – i.e. people whose thoughts and ideas are contrary to common beliefs and who follow their own ideas entirely independent of the field. Therefore, people like Nils Birbaumer in Tübingen and Rüdiger Wehner in Zürich were important for me to see that following your own way and ideas is the way to go.

(more…)

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Squid

Posted by , on 29 July 2011

The winner of the fourth round of Development cover images, collecting more than half of the total votes, was this squid embryo image, taken by Amber O’Connor from the University of Alabama at Birmingham.

Runners-up in this round of images (all taken by participants of the Woods Hole Embryology course in 2010) were a fly image by Sylvia Bonilla (Purdue University) and Mazdak Lachidan (Samuel Lunenfeld Research Institute, Toronto), a mouse image by Elsa Denker (Sars International Centre for Marine Molecular Biology, Bergen) and a Ciona image by Qinwen Liu (University of Maryland, College Park) and Xinwei Cao (St. Jude’s Children’s Research Hospital).

Amber’s image will be on the cover of Development some time in the coming months. Meanwhile, you can download another squid as your August desktop:

The desktop calendar for August, is now up, featuring the runner-up from the first Development cover image voting round of images taken at the 2010 Woods Hole Embryology course. It shows a squid embryo with DAPI staining in blue and phalloidin in red. The image was taken by Jennifer Hohagen of Georg-August-Universitaet in Göttingen.

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

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Post-doc position: Canada

Posted by , on 28 July 2011

Closing Date: 15 March 2021

I currently have an opening in my research group for a post-doc to investigate the development of the vertebrate skeleton.  Our lab studies the development of the neural crest derived skeleton in a comparative manner in chicken and fish embryos (zebrafish and Mexican tetra).   This position will focus on the signals involved in the patterning of skeletal elements in one or more of these animals and the interactions between neural crest and mesodermal tissues.  Applicants who have recently completed a PhD, have experience in molecular biology, developmental and cell biology are strongly encouraged to apply.  

MSVU is an undergraduate university on the East Coast of Canada in beautiful Nova Scotia.  Although a small university, I have a large research group.  This position offers opportunities to interact with a growing research group of undergraduates and graduate students in a well equipped CFI funded lab.  In addition, opportunities to teach, train undergraduates/graduate students and to help manage my lab will be available.  

If you want to hone your teaching and management skills, as well as engage in exciting research then this position might be for you!  Please email a CV, a one page statement of your research experience and interests, and the contact information for three referees to:

Dr Tamara Franz-Odendaal    Tamara.franz-odendaal@msvu.caBiology Dept, Mount Saint Vincent University,

166 Bedford Highway, Halifax, Nova Scotia, B3M 3E4,CANADA

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