It’s been a busy year for EuroStemCell: Europe’s stem cell hub – see www.eurostemcell.org for more information on who we are. We’d like to wish The Node community a happy festive season and a great start to 2012. But before we say goodbye to 2011, we thought you might be interested to know about some of the things we’ve been doing recently…

EuroStemCell goes multilingual

Research updates from EU-funded stem cell projects

Our research updates keep you informed about progress in public-funded European stem cell research. Here’s a recent example from our partner, NeuroStemcell.

Using stem cells to develop new therapies for Parkinson’s and Huntington’s diseases

NeuroStemcell brings stem cell biology and clinical science together to develop and test new approaches to stem-cell-based therapy. We study Parkinson’s (PD) and Huntington’s (HD) diseases, which are degenerative diseases of the brain.

Read more about NeuroStemcell

Italy meets the UK to discuss the future of stem cells in the clinic

Inside the lab

We’ve got two new guest bloggers on our site: Anestis Tsakiridis is sharing his insider’s view of stem cell research in his blogs, Behind the Bench: A series about researchers and their rituals; and we’re delighted to welcome Alzheimer’s researcher Selina Wray, who posted her first blog, A fish out of water, on our site just last week.

Meet the stem cell scientists

We’ve also been busy talking to experts across the stem cell field. Read our interviews with Cedric Blanpain, Yann Barrandon, Christine Mummery, Doug Sipp, Karen English and Nick Barker on the site now and keep your eye out for our chats with Jane Visvader, Connie Eaves and others in the New Year.

Stem cell factsheets

Keep up with Europe’s stem cell news

Sign up to our newsletter to stay in touch with all the latest news from the EuroStemCell project. From February 2012 we’ll be sending out a  monthly newsletter. For more regular updates, you can follow us on Twitter, check out our Facebook page or subscribe to our RSS feeds.  And if you haven’t visited the site for a while, do take a look and get in touch with your feedback and ideas.

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This book review originally appeared in Development. Neil Singh and Ludovic Vallier review “Human Stem Cell Technology and Biology” (Edited by Gary S. Stein, Maria Borowski, Mai X. Luong, Meng-Jiao Shi, Kelly P. Smith and Priscilla Vasquez).

Book info:
Human Stem Cell Technology and Biology: A Research Guide and Laboratory Manual Edited by Gary S. Stein, Maria Borowski, Mai X. Luong, Meng-Jiao Shi, Kelly P. Smith, Priscilla Vasquez Wiley-Blackwell (2011) 419 pages ISBN 978-0-470-59545-9 £93.50/€112.20 (hardback)

Do we need another book on human stem cell biology? The field is fairly long in the tooth now, thirteen years after Thomson first derived human embryonic stem (ES) cells (Thomson et al., 1998). There are many books that cover the theoretical aspects of the discipline (Oderico et al., 2004) and others that attempt to collate protocols useful to human stem cell biologists (Sullivan et al., 2007). Nevertheless, the new book Human Stem Cell Technology and Biology succeeds in combining both of these characteristics, providing not only a clear account of the scientific discoveries underpinning human stem cell biology, but also a useful range of laboratory protocols. The end product may be less comprehensive than Lanza’s classic text (Lanza et al., 2009), but it is perhaps more manageable and appropriate for a newcomer to the field or for an early career scientist working with human pluripotent cell lines for the first time.

The editors are all based at the Center for Stem Cell Biology & Regenerative Medicine at the University of Massachusetts Medical School. The individual chapters are written predominantly by scientists from institutes on the East coast of the United States, although some contributors are based in Australia, Canada and China. The book is divided broadly into five sections: an introduction; two sections on the culture and characterisation of human pluripotent stem cells; and two sections covering more recent technologies and applications relevant to human ES cells.

In the introduction, the authors have managed to distill over 50 years of stem cell advances in just a few pages of text. Although this may be too short for experienced scientists hoping for a colourful narrative history of each breakthrough, we think it does well to bring even novice readers up to speed with current thinking in stem cell biology, from the bottom up.

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How do you make an eye? One early trigger for eye formation in Xenopus, as a new Development paper from Michael Levin’s lab shows, is a small change in bioelectric signals. In fact, that trigger alone is enough to induce eye development in other parts of the body.

In an experiment that measured regions of hyperpolerization in the developing Xenopus embryo, the researchers found two small hyperpolarized spots in the anterior neural field – exactly where the eyes are later formed. Was this change in transmembrane potential (V_mem) related to eye development? To find out, the group carried out a series of experiments to show that the hyperpolarized cells were indeed the same cells that later formed the eye. Not only that, but depolarizing these cells disrupted eye development, suggesting that the transmembrane potential is part of a required signalling mechanism for eye formation.

Eye development involves the formation of an “eye field” from a region of the anterior neural field. This is regulated by eye field transcription factors (EFTFs) such as Pax6 and Rx1. Levin and his colleagues demonstrated that the transmembrane potential in the eye field regulates expression of these EFTFs. When they depolarized the hyperpolarized cells in the eye field, expression levels of Pax6 and Rx1 went down, which explains why eye development was affected upon depolarization.

But what happens if you alter the V_mem not just in the region where eyes are normally formed, but in other parts of the body? To test this, the researchers globally disrupted the V_mem by introducing dominant negative potassium channel subunits into all four blastomeres of four-cell embryos. Within the eye region, the results were as before: many of the embryos did not form functional eyes in the eye region when the V_mem was disrupted. And outside of the eye region? After just changing the transmembrane potential, eyes started to pop up in different parts of the body! Several of the embryos now developed eye tissue in the gut area, and these ectopic eyes have morphological characteristics very similar to regular, functional, eyes.

Ectopic eye, with lens, formed on a tadpole’s gut.

Eye formation caused by a change in transmembrane potential outside of the eye region was also associated with an upregulation of the expression of eye field transcription factors Pax6 and Rx1, suggesting that a bioelectric signal alone is sufficient to initiate the molecular mechanisms required for eye development.

So why don’t we have eyes everywhere? In the discussion section of the paper, the authors hypothesize that a narrow, specific, range of V_mem is associated with the development of particular tissues. This suggests that the eye region is the only area where the V_mem is at the optimal level to upregulate the required transcription factors at the right moment in development to form an eye.

Bioelectric signals also control other physiological processes, such as cell migration and wound healing, but this is the first study that shows a role of bioelectric parameters in eye development.

Development is more than gene regulation alone, and we’re slowly starting to find out all the mechanisms and processes that work together to form organs and organisms.

Pai, V., Aw, S., Shomrat, T., Lemire, J., & Levin, M. (2011). Transmembrane voltage potential controls embryonic eye patterning in Xenopus laevis Development DOI: 10.1242/dev.073759

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Here are the highlights from the current issue of Development:

Balanced ephrin/Eph signals drive topographic mapping

During development of the retinotectal axonal projection, which connects the retina to the optic tectum in the midbrain, the axons of neighbouring retinal ganglion cells project to neighbouring positions in the optic tectum (topographical mapping). However, although retinal fibres rigidly target their destinations in some experimental circumstances, in others they adapt to grossly diverse targets. Here (see p. 335), Franco Weth and colleagues present a surprisingly simple model that explains these hitherto puzzling discrepancies. In this model, topographical axonal mapping relies solely on the balance of forward and reverse signalling by the ephrin/Eph family of guidance molecules. To test their model, the researchers develop a novel ephrin/Eph (double-cue) stripe assay and show experimentally that the simultaneous presence of forward and reverse ephrin/Eph signalling is indeed sufficient for appropriate topographic growth decisions in chick embryonic nerve fibres. Moreover, using computer simulations, they show that their new model is capable of reproducing the discrepant data collected over the years on topographic mapping by the retinotectal axonal projection.

Complex dance of eye morphogenesis unveiled

Optic cup morphogenesis (OCM), which generates the basic structure of the vertebrate eye, is usually depicted as a series of epithelial sheet folding events but experimental evidence to support this stepwise model is lacking. Now, Kristen Kwan, Chi-Bin Chien and colleagues investigate the cellular dynamics of OCM in zebrafish by combining four-dimensional time-lapse imaging and cell tracking (see p. 359). The researchers show that OCM depends on a complex set of sometimes unanticipated cell movements that are coordinated between the prospective neural retina, retinal pigmented epithelium and lens, the tissues that comprise the mature optic cup. Using their cell tracking data, the researchers construct subdomain fate maps for these three tissues that might provide clues to developmental signalling events. Finally, they show that similar movements occur during chick eye morphogenesis, which suggests that the complex choreography of cell movements that shape the vertebrate eye is conserved. These new insights into eye development could, therefore, help to improve our understanding of human eye defects.

Shedding light on Rho kinase signalling

Small-molecule inhibitors can be used as loss-of-function tools to investigate the molecular mechanisms of development but, although exposure to these inhibitors can be temporally controlled, their effects are not spatially restricted. Now, Nanette Nascone-Yoder and colleagues have generated a pharmacological agent that allows for photoactivatable, and hence spatiotemporally limited, inhibition of Rho kinase (see p. 437). Rho signalling is involved in many morphogenetic events, including primitive gut elongation in Xenopus embryos. The researchers install a photolabile ‘caging’ group on Rockout, a small-molecule inhibitor of Rho kinase, and show that caged Rockout (cRO) can permeate Xenopus embryonic tissues. When cultured in the dark, cRO-treated embryos develop normally, but UV irradiation of the right side of these embryos produces animals with a unilaterally shortened gut. Finally, the use of cRO reveals a differential requirement for Rho signalling on the left and right sides of the gut during intestinal rotation. Photocaging pharmacological inhibitors, the researchers conclude, might be a generalisable technique for producing loss-of-function reagents for use in multiple developmental contexts.

The eyes have it: bioelectric induction

Endogenous steady-state ion currents, voltage gradients and electric fields produced by ion channels and pumps regulate patterning and have been implicated in adult eye wound healing. So might they play a role in eye development? On p. 313 Michael Levin and co-workers report that transmembrane voltage potential (V_mem) is an important component of the eye induction cascade in Xenopus. The researchers identify a hyperpolarised cluster of cells in the anterior neural field of Xenopus embryos and show that depolarisation of the lineages from which these cells are derived results in malformed eyes. Remarkably, given our understanding of lineage restrictions and plasticity, manipulation of V_mem in non-eye cells induces ectopic eye formation far outside the anterior neural field. Other experiments show that a Ca²⁺ channel-dependent pathway transduces the V_mem signal and regulates the pattern of eye field transcription factor expression. This new information on the roles of voltage gradients as mediators of patterning during embryogenesis might have implications for the development of regenerative approaches to ocular diseases. (See also this post on the Node.)

Heads up for neural specification

During mouse embryogenesis, the anterior ectoderm develops into neural derivatives (the forebrain) and non-neural derivatives (the cephalic non-neural ectoderm). On p. 423, Kirstie Lawson, Anne Camus and co-workers use single-cell labelling and gene expression analysis to provide new insights into this cell fate choice. At late gastrulation, they report, the expression patterns of anterior ectoderm genes overlap significantly and correlate with areas of prospective fate but do not define lineages. They show that the rostral limit to forebrain contribution is more distal than previously reported. Finally, they report that some precursors of the anterior neural ridge, a signalling centre that is involved in forebrain development and patterning, are clonally related to neural ectoderm and are dispersed over a broad area of the anterior ectoderm where neural precursors also reside. Together, these results suggest that, although the segregation of neural and non-neural cells in the anterior ectoderm is incomplete at the gastrulation stage, there are elements of regionalisation in this tissue that preconfigure the organisation of the head.

ROCK solid epithelial organisation

The basement membrane is essential for epithelial tissue organisation and function but what restricts the basement membrane to the basal periphery of epithelial tissues and what are the basement membrane-mediated signals that regulate coordinated tissue organisation? On p. 411, Melinda Larsen and colleagues use cultures of embryonic mouse submandibular salivary glands to investigate these questions. They show that inhibition of the Rho kinase ROCK in these cultures results in basement membrane accumulation throughout the epithelial compartment. ROCK-mediated control of Par-1b localisation in the outer basal epithelial cell layer (which produces basement membrane) is responsible for normal basal basement membrane positioning, they report. Moreover, inhibition of Par-1b kinase activity prevents basement membrane deposition and disrupts tissue organisation. Conversely, overexpression of Par-1b drives ectopic basement membrane production. These and other results suggest that Par-1b is a master regulator of basement membrane deposition in developing salivary glands and that ROCK control of Par-1b function is essential for normal epithelial integrity and organisation.

PLUS…

When cell cycle meets development

The recent Company of Biologists workshop ‘Growth, Division and Differentiation: Understanding Developmental Control’, which was held in September 2011 at Wiston House, West Sussex, UK. Kaldis and Richardson   review the common themes that emerged from the meeting, highlighting novel insights into the interplay between regulators of cell proliferation and differentiation during development.

See the Meeting Review on p. 225

Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development

Mammalian palatogenesis is a highly regulated morphogenetic process, the complexity of which is reflected by the common occurrence of cleft palate in humans. Here, Bush and Jiang review major advances in our understanding of the mechanisms that control secondary palate development.

 See the Review Article on p. 231

Shaping sound in space: the regulation of inner ear patterning

Groves and Fekete review recent studies of inner ear development and patterning, which reveal that multiple stages of ear development are orchestrated by gradients of signaling molecules.

See the Review Article on p. 245

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VI LASDB Meeting Montevideo 2012 NEWS

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This book review originally appeared in Development. Lance Davidson reviews “Mathematical Models of Biological Systems” (by Hugo van den Berg).

Book info:
Mathematical Models of Biological Systems By Hugo van den Berg Oxford University Press (2010) 256 pages ISBN 978-0-19-958218-1 (paperback), 978-0-19-958219-8 (hardback) £27.50/$49.50 (paperback), £65/$117 (hardback)

One of the key goals of modern cell and developmental biology is to expose the underlying principles that drive cell differentiation and to elucidate how organisms construct functional multicellular structures. Thanks to advances in sequencing, high throughput screens and sophisticated imaging technologies, these fields are now awash with quantitative descriptions of gene transcription, cell signaling and cell mechanics. However, extracting key principles from the flood of new data is a major challenge for researchers and a central obstacle to fundamental progress in cell and developmental biology. The tools required to interpret this vast amount of biological data and to test hypotheses based on these studies can be found in quantitative analysis and mathematical modeling. With the book Mathematical Models of Biological Systems, Hugo van den Berg aims to contribute to the training of a new generation of biologists and mathematicians and to provide them with an introduction to the methods that are now available to quantitatively analyze biological data.

Like many quantitative biologists, my first exposure to mathematical modeling was not in the context of cell biology or developmental biology, but came through examples from physical chemistry, physiology and population ecology. In these fields, simple problems can be formulated using ordinary differential equations (ODEs) with complete statements of the state variables, such as initial conditions. As students, we learned to write ‘word-models’ and to translate these into sets of ODEs. Word models are narrative passages intended to translate the details of a biological problem such that biologists and mathematicians alike can understand the problem in a way that allows equations to be written which capture those details. For instance, we can distil the interactions between predators and prey by stating the rules that govern their populations. Rules that govern the population of prey might include sources of population growth, such as birth or migration, and losses to the population due to predation or disease. The precise statement of these rules should be complete enough to govern the mathematical formulation of the model. Given a well-defined word model, the mathematical biologist can then write a series of ODEs; for example, with variables that represent the number of predators and prey and equations to describe how populations of predators and prey change. As students, we sometimes discovered that there were closed form solutions of these ODEs, in which changes in variables can be predicted explicitly by equations. But more often we found that we could only evaluate the general dynamic behavior of the variables; for instance, whether populations of predators and prey are stable or not. The insights and training that these model-building exercises gave us were instrumental in becoming fluent in the basic skills of mathematical modeling. The processes of formulating a model and relating fundamental principles to the mathematics and experimental outcomes were often more informative than the solution itself. However, after marveling at the awesome power of ODEs, we soon realized that the solution of some, or indeed most sets of, ODEs was intractable, that there was no way to capture relevant details of complex biology with continuous variables, or that model predictions could not be tested experimentally. As such, the tool kit of ODEs used to learn the skills of mathematical modeling is less useful for developing the quantitative models that are needed to describe problems in cell and developmental biology.

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Dates for your calendar
This is a selection of upcoming dates of interest, but it’s by no means an exhaustive list. We’ll try to do these once in a while, but don’t hesitate to write your own posts to let people know about similar deadlines, or leave a comment below. Also make sure to check eligibility before applying.

Conference Registration now open:
–ISSCR meeting (June 13-16, 2012)
–BSDB meeting (April 15-18, 2012)
–LASDB meeting (April 26-29, 2012) – early deadline closes December 12!
-Keystone: The Life of a Stem Cell: From Birth to Death (Mar 11-16, 2012) – early deadline closes January 11, Abstract deadline closes December 13.
-Keystone: Non-Coding RNAs with Eukaryotic Transcription (Mar 31-Apr 5, 2012) – early deadline closes January 30, Abstract deadline closes January 5
-EMBO: Plant development and environmental interactions (27 – 30 May, 2012) – registration and abstract submission closes February 15.
-EMBO: 30 Years of Wnt Signaling (27 June – 1 July, 2012) – Pre-registration & abstract submission deadline: 29 February 2012

Courses:
-SDB-LASDB 4th PASI short course A Systems Biology Approach to Understanding Mechanisms of Organismal Evolution
April 16-25, 2012 in Montevideo, Uruguay (Note, this is right before the LASDB conference at the same location.)
Application deadline is December 15, 2011
-EMBO Practical Course in Advanced Optical Microscopy (March 21-31, 2012) – General application deadline Friday 20 January 2012. Deadline for visa-dependent students 31 December 2011
-EMBO Laboratory Management Courses for postdocs and for independent group leaders. Held at various times during the year in the UK and Germany. Still spots left at some of the courses.
-For those of you in or near the UK, the Royal Society is hosting several Media and Communication Skills Courses for scientists.

Travel fellowships:
-The next round of The Company of Biologists travel fellowships closes December 31st. The funds can be used for a short research exchange in another lab. Postdocs and PhD students (from all countries) can apply.

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This book review originally appeared in Development. Ilan Davis reviews “Molecular Biology of RNA” (by David Elliot and Michael Ladomery).

Book info:
Molecular Biology of RNA By David Elliot, Michael Ladomery Oxford University Press (2010) 460 pages ISBN 978-0-19-928837-3 £34.99/$55 (paperback)

Following the discovery of the structure of DNA and during the early days of molecular biology, RNA was considered to be a less interesting cellular component to study than DNA. This was primarily because RNA was thought to be simply a molecular photocopy of the genetic blue print stored in DNA. But how things have changed! Since those early days, our understanding of the cellular roles of RNA has changed radically. RNA is now considered to be of central importance to both molecular biology and cellular function. Far from only containing genetic information, RNA is now regarded to have credible catalytic properties through the availability of its 2′-OH, a reactive group that replaces a non-reactive ‘O’ atom in DNA. Moreover, its catalytic roles include key functions in the most important molecular machines of the cell, such as the spliceosome and ribosome. In hindsight, it would perhaps not be so surprising if the RNA world hypothesis turned out to be correct. This hypothesis states that the first life forms on our planet were RNA-based simple cells in the pre-biotic soup. RNA is certainly a better candidate than either DNA or proteins for a self-replicating molecule that acts both as a template for, and that has the necessary catalytic machinery to perform, its own replication. Moreover, the discovery that most mRNAs are spliced, and the gradual uncovering of a breathtaking number of ways in which gene expression is regulated post-transcriptionally, have meant that the field of RNA has undergone rapid growth in the past few decades. This rapid growth has recently increased even further because of the discovery of RNA interference (RNAi), as well as the discovery that small RNAs, distinct from tRNA and snRNA, undergo processing to fulfil a range of cellular functions. These include the regulation of transposable element transposition by piRNAs, regulation of translation by microRNAs and still poorly explored large non-coding RNAs (ncRNA). Many of these ncRNAs have turned out to have important roles in development and during disease processes, such as cancer. Therefore, it is clear that all aspects of RNA molecular biology have now become central to our understanding of cell and developmental biology.

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Satellite cells are muscle stem cells that regenerate injured muscle (remember this earlier post?).  They are highly motile cells that may be able to travel in order to repair injured muscle far away, and a recent paper in Development describes the role of Eph/ephrin signaling in satellite cell motility and patterning.

One of the most well-understood guidance pathways is the Eph/ephrin pathway, which has major roles in cell migration and axon guidance throughout development.  In this pathway, Eph receptors on one cell interact with ephrin ligands bound to another cell’s membrane.  This interaction typically causes rapid changes in the Eph-expressing cell’s adhesion and cytoskeletal organization, and frequently causes the cells to repel each other.  A recent paper describes the role of Eph/ephrin signaling in satellite cell motility and patterning.  Stark and colleagues showed that ephrin ligands are differentially localized to healthy and regenerating muscle tissue, and used a well-established “stripe assay” to show that ephrins can repel mouse satellite cells.  As seen in the images above (increasing magnification from left to right), stripes of ephrin-B1 ligand (bottom row, blue stripes) repulsed the satellite cells, compared to the distribution of cells on control stripes (top row).  In addition, Stark and colleagues explanted mouse satellite cells into the hindbrain of developing quail embryos, from which neural crest cells emigrate using Eph/ephrin signaling.  Some satellite cells migrated along with the neural crest cells and conformed to the same boundaries.

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

Stark, D., Karvas, R., Siegel, A., & Cornelison, D. (2011). Eph/ephrin interactions modulate muscle satellite cell motility and patterning Development, 138 (24), 5279-5289 DOI: 10.1242/dev.068411

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