This book review originally appeared in Development. Tatsumi Hirata reviews “Neuronal Guidance: The Biology of Brain Wiring ” (Edited by Marc Tessier-Lavigne and Alex L. Kolodkin).

Book info:
Neuronal Guidance: The Biology of Brain Wiring. Edited by Marc Tessier-Lavigne, Alex L. Kolodkin. Cold Spring Harbor Laboratory Press (2011) 397 pages ISBN 978-0-879698-97-3 $135 (hardback)

As a graduate student, I learned developmental neurobiology from the Principles of Neural Development (Purves and Lichtman, 1985). This masterpiece textbook taught me the fundamental concepts of how neurons are interconnected, vividly described the historical experimental basis, and introduced me to the exciting field of developmental biology. However, this book is obviously out of date today, particularly since a great number of guidance molecules and pathways have been identified in the meantime, so I have had to look for a good alternative for graduate students and postdocs interested in this field. Neuronal Guidance: The Biology of Brain Wiring completely fulfilled my expectations.

As this book specifically focuses on neural guidance, it might not be an appropriate textbook for undergraduate students with a broad interest in developmental biology, but it will provide a very good read for postgraduates who have some experience in neurobiology or who are keen to have a research career in this or related fields. It will also be very useful for senior investigators wanting to catch up with the latest data in the field.

Following a brief primer written by the editors, Marc Tessier-Lavigne and Alex L. Kolodkin, the book is organized into 19 chapters, each contributed by experts on the topic. Initially, I was somewhat afraid that this style might make the book a selective collection of highly specialized reviews, but, thanks to the thoughtful choice of topics and contributors, the book is, in fact, much more comprehensive than I anticipated.

The chapters are grouped into three sections, each on a different aspect of neural guidance. The first chapter, by Jonathan Raper and Carol Mason, is entitled ‘Cellular strategies of axon pathfinding’, and provides a good basic overview of the history of axon guidance research and the general concepts obtained therefrom. The following eight chapters in this first section describe comprehensive guidance strategies in traditional and new models of nervous systems. These include chapters on such as visual map development by David A. Feldheim and Dennis D. M. O’Leary, nervous system midline crossing by Barry J. Dickson and Yimin Zou, and dendrite and axon tiling by Wesley B. Grueber and Alvaro Sagasti. A little unexpected is the inclusion of the chapter entitled ‘Human genetic disorders of axon guidance’ by Elizabeth C. Engle, which effectively provides a fresh perspective on this topic.

The second section of the book includes five chapters dealing with intercellular signaling in neural guidance. This section is more detailed than the first part of the book, and is devoted to the introduction of many molecules and their signaling pathways, reflecting the rapid expansion of this field in recent years. Among the chapters here, ‘Signaling from axon guidance receptors’ is a clear overview presented by Greg J. Bashaw and Rüdiger Klein, and ‘Trafficking guidance receptors’ by Bettina Winckler and Ira Mellman describes a topic that is not always covered in axon guidance books and is informative to read.

The final section introduces other cellular processes that use common guidance signals. Several of these topics are already familiar to developmental neurobiologists, such as those described in the chapters on neural cell migration by Oscar Marín and colleagues, axon pruning by Pierre Vanderhaeghen and Hwai-Jong Cheng, and axon regeneration by Roman J. Giger and colleagues. These authors very successfully provide a good, broad perspective to the reader.

Overall, the selection of topics is well balanced, and the chapters are arranged to accurately represent the current scenario in research on neural guidance. Although a few chapters seem a little too specific for people with interests outside of that particular subdiscipline, most are written in a coherent holistic manner to provide a broad overview of our current understanding of neural guidance.

Some topics are repeatedly discussed in several sections of the book. This is the case with guidance molecules such as netrin, semaphorins, slits and ephrins, which function in various systems. Nevertheless, the overlap in the content between chapters is kept to a minimum. I prefer this approach, as it helps the reader to understand, in a step-by-step manner, how the nervous system is systematically constructed by multiple guidance signals. This makes the book more suitable to providing an understanding of the underlying biology, rather than comprising a thick directory of guidance molecules listed with location and time of action.

One feature that really impressed me is that most chapters devote a lot of attention to historical background and the description of general concepts that have led to the current state of research in the field. As mentioned above, several major principles of neural development were already established by 1985, when the classic text Principles of Neural Development was published, even though support in the form of molecular data was lacking at that time. Surprisingly, the subsequent identification of many guidance molecules and their signaling pathways has barely challenged these classic principles. Rather, new findings have confirmed established models, and, in fact, identification of most guidance molecules was based on general deductions from these principles. For example, the identification of ephrins was inspired by the historic transplantation experiments conducted on the retinotectal system by Roger Sperry and others: researchers looked for the magic chemoaffinity label that, according to theory, would form a ‘gradient’ over the tectum, and identified ephrins, which possessed exactly the predicted properties (Cheng et al., 1995; Drescher et al., 1995). Neuronal Guidance: The Biology of Brain Wiring pleasantly reminded me of such links between historic concepts and the latest data on molecular mechanisms. Realization of such connections will clarify, especially to newcomers in this field, the real significance of ongoing studies.

In summary, Neuronal Guidance: The Biology of Brain Wiring achieves a good balance between basic principles and leading cutting-edge research and will prove to be an excellent introductory text for students and postgraduates who are curious about this branch of developmental biology. The book is also refreshing for old hands: after reading it, I felt full of new ideas.

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Today’s recommended paper is:

Growing Microtubules Push the Oocyte Nucleus to Polarize the Drosophila Dorsal-Ventral Axis
Tongtong Zhao, Owen S. Graham, Alexandre Raposo and Daniel St Johnston (2012)
Science 336 (6084), 999-1003

Submitted by Andrew Renault:
“An example of purely basic research, using beautiful live imaging to overturn previously held ideas about how an oocyte nucleus is repositioned to break radial symmetry.”

From December 1 to 24 we are featuring Node readers’ favourite papers of the past year. Click the calendar in the side bar each day to see a new paper. To see all papers submitted so far, see the calendar archive.

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An interview with Roger Barker

Roger Barker is Professor of Clinical Neuroscience at the Cambridge Centre for Brain Repair, and one of the authors on a recent Development paper from Elena Cattaneo’s group in Italy, about the derivation of functional neurons from human stem cells. EuroStemCell has published a range of videos by several authors involved in this paper, but here we spend a bit more time with Roger Barker to talk about his international collaborations and his work looking at verification of stem cell-derived neurons.  One of the questions is from his EuroStemCell video interview (conducted in collaboration with the Node), and the other two are unique to the Node.

What was your role in this project?

The work that I’ve been doing on this paper with Elena Cattaneo is to look at the normal development of the human striatum. The striatum is particularly important for the work that I do, because the early pathology of Huntington’s disease is found within that structure. Ultimately, what we’re trying to do is to replace the striatal cells, which are lost as part of Huntington’s disease, by some equivalent – whether it be from a stem cell source or a fetal source.

Elena has been very keen to make these cells from a stem cell source and to validate that the cells you get at the end look like the cells that are there in the original state, we’ve looked at the normal development of the human striatal system. This has involved collecting human fetal tissue at different ages and then staging it and staining it for a series of markers to show when the transcription factors and other markers come on as the striatum normally develops. The earliest stage we got was 3-4 week old human fetuses, which then extended up to 11-11.5 weeks. By verifying those markers in normal human development and correlating them with what you see in striatal cells derived from stem cells, you can say whether they are actually one of the same.

Elena Cattaneo’s lab is in Italy, and you’re in the UK. What is the benefit of such an international collaboration in work like this?

One of the great challenges with doing work on stem cells across Europe is the different political landscape in the different countries where the work is actually done. I’m part of a consortium called NeuroStemcell, which links groups of scientists in the United Kingdom with people in Sweden, Germany, and Italy, and is able to allow for valuable human tissue and stem cell expertise to be brought together efficiently across the EU. Of course each country has its own agenda and its own rules with respect to work on fetal tissue and stem cells, which can make this type of work difficult at times.  I also lead a Europe-wide transplant programme for Parkinson’s disease called Transeuro, which is bringing together groups from Germany, France, Sweden, Austria, and the UK to develop a treatment method for Pakinson’s disease using human fetal tissue. Again, there are huge differences in the regulation and use of that tissue between countries.

So on the one hand you have this great ability to bring expertise together across Europe, with all the complementary techniques and abilities to really crack key questions, but you also have to do that in a regulatory context that can make it extremely difficult. One of the outputs from NeuroStemcell, for example, may be to develop a cell therapy from an embryonic stem cell source, which could not then be necessarily used in all the countries in which it was actually developed. But the advantage of NeuroStemcell is that you have this amazing capacity to link resources. In this particular paper, the group in Italy, led by Elena, have such fabulous expertise in developing striatal neurons, but their lack of access to human fetal material makes it very difficult for them to do the project without collaborating with a lab like ours, in a country that does have access to fetal material.  So these are truly international collaborations and without either party the project wouldn’t happen.

How does this work compare to other studies in the same field?

This is a pretty major study, because people have been trying to develop protocols to take human embryonic stem cells through to striatal DARPP-32-positive neurons for a while. Of course, as in a lot of areas in this field, people always make claims that they’ve achieved this, but often the data are not quite as robust as they first seem.

In the early days of stem cell biology, verification of the final cell type derived from a stem cell usually only involved testing for a single marker, but now the requirements extend beyond this. Now one wants to see that the cell not only expresses the marker that you’ve defined as being of paramount interest, but all the other markers which are evidence that the derived cells is equivalent to the mature native cell. This is where the developmental study we’ve done with human fetal material is very helpful as it shows that the stem cell derivatives follow and express all the markers found in normal development. In addition it is also necessary to show that the derived neurons are electrically active in a way that you’d expect and has the neurophysiological signature of the cell we’re interested in- in this case DARPP-32 striatal neurons. Finally it is important to show not only that the cells look neurophysiologically, developmentally and anatomically like their host equivalent, but that on grafting they can be integrated into a circuit in the appropriate fashion.

Trying to make these striatal cells has been a major challenge in the field. There was a paper either earlier this year in Cell Stem Cell in which the authors claimed that they had produced a similar cell to the one that we have in this paper.  I think, again, that the extent to which it is exactly the same as the type of cell we’ve produced is debatable.

These type of verification experiments are very important, because there is now a great desire to try these cells in clinical trials, but we only want to do that if we’re absolutely convinced that the cell we have is the cell we think we have.

Article:
Carri A.D., Onorati M., Lelos M.J., Castiglioni V., Faedo A., Menon R., Camnasio S., Vuono R., Spaiardi P. & Talpo F. & (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

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Today’s recommended paper is:

Transcription in the Absence of Histone H3.2 and H3K4 Methylation
Martina Hödl and Konrad Basler (2012)
Current Biology 08 November 2012

Submitted by Barry Thompson:
“This paper overturns the dogma that H3K4 methylation is essential for activation of gene transcription in response to many different signaling pathways.”

From December 1 to 24 we are featuring Node readers’ favourite papers of the past year. Click the calendar in the side bar each day to see a new paper. To see all papers submitted so far, see the calendar archive.

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Here are the highlights from the current issue of Development:

Against the segmentation clock

A gene expression oscillator called the segmentation clock controls the periodic formation of somites in vertebrate embryos. In zebrafish, negative autoregulation of the transcriptional repressor genes her1 and her7 is thought to control the clock’s oscillations. Delays in this negative-feedback loop, including transcriptional delay (the time taken to make each her1 or her7 mRNA) should thus control the clock’s oscillation period. On p. 444, Ertuǧrul Özbudak, Julian Lewis and colleagues report that, unexpectedly, mutants in which only her1 or her7 is functional have almost identical segmentation clock oscillation periods – because the her1 and her7 genes are very different lengths, the researchers had anticipated that the two mutants would have different transcriptional delays and thus different oscillation periods. The researchers resolve this paradox by showing that the RNA polymerase II elongation rate is extremely fast in zebrafish embryos. They suggest, therefore, that the time taken for her1 and her7 transcript elongation is relatively insignificant, and that other sources of delay (e.g. splicing delay) may instead determine the oscillation period.

Non-catalytic role for Mmp14 in stromal invasion

During mammary gland branching morphogenesis, mammary epithelial cells (MECs) invade the surrounding stroma. Here (p. 343), Mina Bissell and co-workers investigate whether the matrix metalloproteinase Mmp14, which is expressed in mammary glands during branching and which has a key role in cancer cell invasion, is involved in branching morphogenesis. The researchers report that the catalytic activity of Mmp14 is required for MEC branching in dense but not sparse three-dimensional collagen gels, but that, surprisingly, a non-proteolytic function of Mmp14 is required for branching in both conditions. They show that silencing Mmp14 reduces the levels of integrin β1 (Itgb1), which is required for branching in vivo, and that Mmp14 associates directly with Itgb1 through a transmembrane/cytoplasmic domain in Mmp14. Notably, this non-catalytic domain is required for branching in collagen gels. These results indicate that non-proteolytic activities of Mmp14 modulate the Itgb1-dependent signals that mediate MEC invasion during branching morphogenesis and provide a possible explanation for why cancer therapy drugs that target Mmp14’s catalytic function have failed in clinical trials.

Bioelectric signals size up regeneration

Regenerative medicine aims to replace lost or damaged tissues and organs with functional parts of the correct size and shape. To achieve this goal, we need to understand what determines the scale and form of regenerating tissues. Michael Levin and colleagues have been tackling this issue by investigating the regulation of organ size during planarian regeneration (see p. 313). During this process, existing tissues are remodelled concurrently with new tissue growth to maintain the correct relative tissue proportions. The researchers show that, in Schmidtea mediterranea, membrane voltage-dependent bioelectric signalling determines head size and organ scaling during regeneration. Specifically, RNA interference of the H⁺,K⁺-ATPase ion pump causes membrane hyperpolarisation and produces regenerated animals with shrunken heads and oversized pharynges, but does not inhibit the production of new tissue (blastema). Other experiments indicate that the H⁺,K⁺-ATPase ion pump maintains proportionality during regeneration by mediating apoptotic sculpting of the original tissues. Thus, bioelectric signalling regulates the cellular mechanisms that control organ size and shape during regeneration.

Fat-tening up planar cell polarity

The conserved atypical cadherin Fat regulates planar cell polarity, but the mechanisms by which Fat controls cell shape and tissue organisation are unclear. Emily Marcinkevicius and Jennifer Zallen (p. 433) now show that Fat is required for the planar polarised organisation of denticle precursors, adherens junction proteins and microtubules in the Drosophila embryo epidermis. Adherens junction remodelling and cell shape are disrupted in fat mutants, they report, and in flies carrying mutations in Expanded (a regulator of the Hippo pathway) and in Hippo and Warts (two kinases in the Hippo pathway). Mutations in the Hippo/Warts pathway do not recapitulate the effects of Fat loss on denticle planar organisation, however, and the cell shape and planar polarity defects in fat mutants do not require transcriptional regulation by Yorkie, a target of the Hippo pathway. These results suggest that a common upstream signal provided by Fat regulates junctional and cytoskeletal planar polarity in the Drosophila embryo and that Fat influences tissue organisation by regulating polarised junctional remodelling.

Recapitulating striatal neurogenesis

Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons and are among the first neurons to degenerate in Huntington’s disease. Here (see p. 301), Elena Cattaneo and co-workers report that human pluripotent stem (hPS) cells can be induced to differentiate into MSNs using an ontogeny-recapitulating protocol. The researchers induce ventral telencephalic specification of hPS cells in feeder-free adherent cultures using BMP/TGFβ inhibition followed by sonic hedgehog/WNT pathway modulation. They then induce terminal differentiation of the telencephalic progenitors in the presence of brain-derived neurotrophic factor, thereby generating MSNs that express DARPP-32 and other striatal markers. These MSNs carry dopamine and adenosine receptors, elicit a typical firing pattern, and show dopamine-dependent neuromodulation and synaptic integration ability in vivo. Finally, when transplanted into the striatum of a rat model for Huntington’s disease, hPS cell-derived neurons survive and correct motor deficits. This ontogeny-recapitulating method provides a platform for human neurodevelopmental biology studies, suggest the researchers, and could be used to develop a Huntington’s disease model for drug screening.

Cell-cycle pattern predicts stem cell fate

Cell-cycle progression and lineage commitment of stem cells seem to be tightly linked but it has not been possible to study this relationship in live stem cells. Now, Matthias Lutolf and colleagues (p. 459) describe a single-cell tracking approach that enables the automatic detection of cell-cycle phases in live stem cells that express fluorescent ubiquitylation-based cell-cycle indicator (FUCCI) probes. The researchers use their approach to identify distinctive changes in the length of cell-cycle phases and in the fluorescence intensity of the G₁ (red) and S/G₂-M (green) FUCCI probes during the differentiation of adult neural stem/progenitor cells (NSCs) and embryonic stem cells. Moreover, they use these changes in fluorescence intensity to purify NSCs from a heterogeneous population and to increase the proportion of reprogrammed cells obtained during NSC reprogramming to an induced pluripotent stem cell-like state. These findings shed new light on the relationship between cell-cycle progression and cell fate choice and introduce a tool that could advance our understanding of stem cell biology.

Plus…

DEVELOPMENT AT A GLANCE: Phyllotaxis

The precise arrangement of plant organs, also called phyllotaxis, has fascinated scientists from multiple disciplines. In this Issue, Jan Traas reviews new insights into the regulation of phyllotactic patterning and provides an overview of the various factors that can drive these robust growth patterns. See the Development at a Glance poster article on p. 249

Adhesion in the stem cell niche: biological roles and regulation

Stem cells are often anchored to their niche via adhesion molecules. However, as reviewed here by Xie and colleagues, recent studies have revealed other important roles for adhesion molecules in the regulation of stem cell function. See the Review article on p. 255

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Today’s recommended paper is:

Cilia at the Node of mouse embryos sense fluid flow for left-right determination via Pkd2
Satoko Yoshiba et al.
Science 338 (6104), 226-231

Submitted by Benoit Bruneau:
“Left-right asymmetry is well studied but important mysteries have remained unsolved. This paper finally seals the deal on the importance and mechanistic role of the nodal cilia of the mouse in establishing the initial signaling that launches the LR cascade.”

From December 1 to 24 we are featuring Node readers’ favourite papers of the past year. Click the calendar in the side bar each day to see a new paper. To see all papers submitted so far, see the calendar archive.

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I am a second year graduate student in Department of Chemical and Biological Engineering, Princeton University. I got a chance to visit Center for Mathematical Biology, Mathematical Institute, University of Oxford this November. I would like to thank Company of Biologist’s Traveling Fellowships program and people behind it for supporting me. It was an amazing and enriching visit.  We ( Prof. Stanislav Shvartsman’s Lab) work on Drosophila (fruit fly) Oogenesis and Embryogenesis. The focus of this trip was discussing the modelling aspect of Epithelial morphogenesis specifically formation of respiratory appendages during Drosophila Oogenesis. Discussions were very fruitful and we came up with some good ideas. I am currently working on them.  I will share with all of you more about the work ,once this project comes to its logical conclusion of a research article.

Once again I would like to thank Company of Biologist for the Traveling Fellowship.

Best wishes

Mahim

http://www.genomics.princeton.edu/stas/index.htm

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Do you need to learn a new technique?  Are you planning a collaborative visit?  If so please have a look at The Compnay of Biologist’s Travelling Fellowships – http://www.biologists.com/fellowships.html.  The next deadline is the 31st December 2012.

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Today’s recommended paper is:

A system of repressor gradients spatially organizes the boundaries of Bicoid-dependent target genes.
Hongtao Chen, Zhe Xu, Constance Mei, Danyang Yu and Stephen Small (2012)
Cell 149 (3), 618-629

Submitted twice – by Andrew Renault and by Seema Grewal.

Andrew: “How morphogens create robust and discrete responses has been a long standing question. This paper nicely shows that the correct order of Bicoid target gene boundaries depends on a system of transcriptional repressors, reinforcing the notion that antagonistic mechanisms are critical for morphogen function”

Seema: “This paper challenges the idea that Bicoid acts as a simple morphogen.”

From December 1 to 24 we are featuring Node readers’ favourite papers of the past year. Click the calendar in the side bar each day to see a new paper. To see all papers submitted so far, see the calendar archive.

(1 votes)

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Today’s recommended paper is:

Specifying and Sustaining Pigmentation Patterns in Domestic and Wild Cats
Christopher B. Kaelin, Xiao Xu et al. (2012)
Science 337 (6101), 1536-1541

Submitted by Heather Etchevers:
“I am interested in skin development and pigmentation. But this paper was justifiably published in a general science journal because to some extent, everyone has asked themselves the question of how the leopard got its pattern of spots – in some form or another. The technical approaches in this paper started classical and then used a nearly impossible model to test its conclusions: rare mutant, endangered felid samples from captive animals, and used as controls an impressive number of samples from wild animals. It makes for a good read and clearly leaves avenues open for further exploration.”

From December 1 to 24 we are featuring Node readers’ favourite papers of the past year. Click the calendar in the side bar each day to see a new paper. To see all papers submitted so far, see the calendar archive.

(1 votes)

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