This editorial by Development Editor-in-Chief Olivier Pourquié appears in the current issue of Development.

It seems most appropriate to start this editorial by congratulating the 2012 winners of the Nobel prize, John Gurdon and Shinya Yamanaka, for their work on stem cells and reprogramming. We at Development are particularly proud of this prize as John Gurdon published his original paper on the reprogramming of the frog oocyte nucleus to a totipotent state – the work that led to this award – in 1962 in the Journal of Embryology and Experimental Morphology (Gurdon, 1962), which was to become Development in 1987. Furthermore, John Gurdon was, until 2011, the Chair of The Company of Biologists, the charity that runs our journal. John Gurdon has been a role model for many of us and his original thinking has stimulated the field for many years and continues to do so.

The discovery that the nucleus of an adult cell can be reprogrammed to a totipotent embryonic state by nuclear transplantation in the frog revealed an unsuspected degree of plasticity of the genome and opened the way to the studies by Shinya Yamanaka on the reprogramming of adult somatic cells by a set of transcription factors (Takahashi and Yamanaka, 2006). Indeed, the experiments of Gurdon and Yamanaka clearly established that the information contained in the DNA of all somatic cells is sufficient to recreate an adult organism. That the nucleus of differentiated cells can be reprogrammed to the pluripotent state of early embryonic cells shows that it is possible to reverse the course of development and differentiation. This work opened tremendous new research avenues into the genetic control of pluripotency and differentiation. The ability to reverse-engineer embryonic cells and their derivatives from an adult counterpart, combined with the recent demonstration that sophisticated organs, such as the retina or hypophysis, can be grown from embryonic stem cells in vitro (Eiraku et al., 2011; Suga et al., 2011), means that recreating human organs in vitro is a real and achievable goal. This should open a new era in which the uncharted territory of human developmental biology will be explored. In addition, it will allow us to produce differentiated cells of all human lineages at all stages of differentiation, raising the possibility of establishing in vitro models of human diseases to study their pathophysiology and to screen for new treatments or cures. Finally, these advances should favour the development of cell therapy and regenerative medicine, potentially allowing the replacement of missing cells of body parts with cells from organs engineered in vitro. These are some of the major challenges that are now within reach thanks to Gurdon and Yamanaka’s discoveries.

In my view, this Nobel prize also beautifully illustrates the mutation that developmental biology is currently experiencing. Both Gurdon and Yamanaka clearly tackled a central question of developmental biology: how the genetic information is deployed during embryonic development to generate the variety of cell types and structures that will compose the adult body, and how this process might be reversed. Still, many scientists, particularly among our younger colleagues, will consider Gurdon and Yamanaka as stem cell biologists rather than developmental biologists. Although this might seem a semantic argument, it has a strong impact on the perception of a journal such as Development. The rapidly growing field of stem cell biology is largely an offshoot of developmental biology. However, it is now becoming independent from the more traditional developmental biology, creating its own structures with new societies and new journals. This reflects a healthy growth in the numbers of stem cell scientists, but it is occurring partly at the expense of the developmental biology community. Thus, while Development is clearly viewed as a community journal for those involved in core areas of developmental biology, feedback suggests that stem cell scientists do not necessarily regard Development in the same way.

I see engagement with the stem cell community as crucial to the future success of Development. As Editor in Chief, I have initiated several actions to raise the profile of the journal within this field. These include the recruitment of expert editors in the field, and creation of the ‘Development and Stem Cells’ section of the journal. Notably, many of our most highly downloaded and cited papers of the past 2 years appeared in this section – a preliminary indication that this move has been a success. In 2013, we hope to intensify our actions to reach out to the stem cell community and establish Development as an important forum for the publication of outstanding papers in this field.

Of course, while I believe that stem cell science is an important and expanding field within developmental biology, we will continue to be the home for more traditional disciplines, as well as for other growing areas, such as quantitative and systems biology, and evo-devo. In addition, when I took over as Editor in Chief, I felt that there was a need for Development to publish papers dealing with techniques of importance to the community. Over the past 2 years, we have published a number of such technical papers, and we are now expanding and renaming this section ‘Techniques and Resources’. We hope that this will provide an ideal home for high-quality papers of a technical nature, or those that describe a new resource, and we welcome your submissions.

Importantly, at the heart of our evolution as a journal, and running through this editorial, is the concept of community. Development is a not-for-profit journal run by scientists for scientists, and it is vital for us to make sure that we are efficiently serving the community of developmental biologists. We are very open to your feedback on what we are doing well (or badly) at the journal, and we will greatly benefit from your support while we move towards these new areas. Our community website the Node (thenode.biologists.com), launched in 2010, is one place where you can share your thoughts on the state of the developmental biology field, on scientific publishing and how Development is doing, or on anything else of relevance to developmental biologists. For those of you not yet familiar with the Node, I encourage you to visit the site and to contribute. For those happier in the real world than the virtual one, you will also find Development editors and staff at meetings throughout the globe and the year, and we’re always happy to talk about the journal and to receive your input.

This year has seen little change in the composition of the team of editors. Ken Zaret decided to step down as an editor and we are extremely grateful for his many years of service at Development and for his hard work to maintain the high quality standards of the journal. Although we are very sorry to see him leave, we were happy to welcome a new editor, Haruhiko Koseki from the Riken Center for Immunology in Yokohama. Haruhiko is a specialist in mouse development and epigenetics. He has joined the group of current editors, which also includes Magdalena Götz, Alex Joyner, Gordon Keller, Thomas Lecuit, Ottoline Leyser, Rong Li, Shin-Ichi Nishikawa, Nipam Patel, Liz Robertson, Geraldine Seydoux, Austin Smith, Patrick Tam and Steve Wilson. I congratulate them for their outstanding work in the past year. I also thank the in-house Development team – particularly Katherine Brown, our Executive Editor, and Claire Moulton, our Publisher – for their excellent support. We look forward to a successful 2013.

(4 votes)

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Here are the highlights from the current issue of Development:

Gut feeling about Wnt doses

The intestinal epithelium continuously renews throughout life. Canonical Wnt signalling – a major player in this renewal – both controls intestinal epithelial proliferation and maintains intestinal stem cells. The existence of a gradient of β-catenin expression along the colonic crypt axis, with the highest β-catenin levels at the bottom where the intestinal stem cells reside, suggests that Wnt signalling might have dose-dependent roles in the colonic epithelium. On p. 66, Yasuhiro Yamada, Konrad Hochedlinger and colleagues use a β-catenin-inducible mouse model to investigate this possibility. High levels of β-catenin expression induce crypt formation but reduce cell proliferation among progenitor cells, they report, whereas lower levels have the opposite effect. Notably, Notch signalling is activated in the slow-cycling crypt cells produced by β-catenin overexpression, and treatment of β-catenin-expressing mice with a Notch inhibitor turns the slow-cycling cells into actively proliferating cells. Together, these results suggest that different levels of Wnt signalling, in cooperation with Notch signalling, control the differentiation and proliferation of the colonic epithelium.

Micro-(RNA)managing muscle repair

Following muscle injury, quiescent muscle stem cells (satellite cells) are activated and then proliferate and differentiate to regenerate myofibres. Wnt signalling regulates the differentiation of activated satellite cells, but what other factors control skeletal muscle regeneration? On p. 31, Francisco Naya and co-workers report that the transcription factor myocyte enhancer factor 2A (MEF2A) plays an essential role in skeletal muscle regeneration in adult mice. Myofibre formation is impaired in injured Mef2a knockout mice, the researchers report, and this impaired injury response is associated with downregulation of the Gtl2-Dio3 locus, the largest known mammalian microRNA (miRNA) cluster. Notably, a subset of the miRNAs in this locus represses secreted Frizzled-related proteins (sFRPs), which are inhibitors of Wnt signalling. Consistent with these data, sFRP expression is upregulated and Wnt activity is attenuated in injured Mef2a knockout muscle. These and other results suggest that miRNA-mediated modulation of Wnt signalling by MEF2A is required for muscle regeneration and suggest that targeting this pathway might enhance the regeneration of diseased muscle.

Epigenetic maintenance via DNA replication machinery

During development, cell type-specific epigenetic states must be duplicated accurately during mitosis to maintain cellular memory. The maintenance of epigenetic memory seems to involve the DNA replication machinery but is poorly understood. Here (p. 156), Yeonhee Choi and co-workers show that INCURVATA2 (ICU2), the catalytic subunit of DNA polymerase α in Arabidopsis, ensures the stable maintenance of histone modifications. Vernalisation, the acquisition of floral competence though exposure to prolonged cold, requires repression of Flowering Locus C (FLC) through accumulation of the histone mark H3K27me3. The researchers show that the missense mutant allele icu2-1 does not affect the recruitment of CLF, a component of polycomb repressive complex 2 (PRC2), and the resultant deposition of the H3K27me3 mark on the FLC locus. However, icu2-1 mutants do not stably maintain this epigenetic mark, which results in mosaic FLC de-repression after vernalisation. ICU2 also maintains repressive histone modifications at other PRC2 targets and at retroelements, and it facilitates histone assembly in dividing cells, which suggests a possible mechanism for ICU2-mediated epigenetic maintenance.

Otx2 switches early pluripotency states

Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) correspond to the naïve ground state of the preimplantation epiblast and the primed state of the post-implantation epiblast, respectively. The ESC state is characterised by spontaneous, reversible differences among the ESCs in their susceptibility to self-renewal and differentiation signals. Here (p. 43), Antonio Simeone and colleagues investigate the mechanisms that control this metastable state and the transition from ESCs to EpiSCs. The researchers report that Otx2, a transcription factor that is required for brain development, is expressed in a large subset of ESCs and maintains the ESC metastable state by antagonising ground state pluripotency and promoting commitment to differentiation. Otx2 is also needed for ESC transition into EpiSCs, they report, and stabilises the EpiSC state in cooperation with BMP4 and Fgf2. Finally, they show that Otx2 is required for the differentiation of ESC-derived neural progenitors. Thus, Otx2 is an intrinsic determinant of the ESC state and of the ESC to EpiSC pluripotency transition.

Sphingosine 1-phosphate stops muscle wasting

Duchenne muscular dystrophy – a lethal disease caused by dystrophin mutations – is characterised by age-dependent muscle wasting. Mario Pantoja and co-workers now report that increased intracellular sphingosine 1-phosphate (S1P) suppresses dystrophic muscle phenotypes in a Drosophila Dystrophin mutant (see p. 136). The researchers use localisation of Projectin protein (a titin homolog) in sarcomeres, as well as muscle morphology and movement assays, to show that reduction of wunen (a homolog of lipid phosphate phosphatase 3, which dephosphorylates several phospholipids in higher animals) suppresses dystrophic muscle defects; wunen is known to suppress a wing vein defect also seen in Drosophila Dystrophin mutants. Hypothesising that wunen-based suppression may be through elevation of S1P, which promotes cell proliferation and differentiation in muscle, the researchers use several genetic approaches and pharmacological agents to raise S1P levels in the dystrophic flies. In each case, increased S1P levels suppress dystrophic muscle phenotypes. The researchers suggest, therefore, that Drosophila could be used to identify small molecules that might suppress muscle wasting in human patients.

A Rosa future for Fucci cell-cycle indicators

Visualising cell-cycle progression in living embryos is essential for improving our understanding of developmental processes. The fluorescent ubiquitylation-based cell-cycle indicator (Fucci), which was generated by fusing the ubiquitylation domains of Cdt1 and Geminin to different fluorescent proteins, has been used to label G₁ and S/G₂/M phase nuclei orange and green, respectively. Cell cycle dynamics during development have been studied in transgenic mice expressing Fucci under the control of the CAG promoter but Fucci expression levels are somewhat variable. Now, Shinichi Aizawa and colleagues (p. 237) describe two new mouse cell-cycle reporter lines that use Fucci2, a Fucci derivative that emits red and green fluorescence. The R26p-Fucci2 transgenic line uses the Rosa26 promoter and harbours the G₁ and S/G₂/M phase probes in a single transgene to ensure their co-inheritance. In the R26R-Fucci2 transgenic line, the two probes are incorporated into the Rosa26 locus conditionally to allow cell-cycle analysis in specific cell types. Time-lapse imaging experiments suggest that both reporter lines hold great promise for studying cell-cycle behaviour in vivo.

Plus…

Endoreplication and polyploidy: insights into development and disease

Polyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. As part of the “Development: The Big Picture” series, Fox and Duronio review the conserved mechanisms that control the generation of polyploidy and highlight studies that have  begun to provide clues into the physiological function of polyploidy. See the Primer on p. 3

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

Cell polarity: models and mechanisms from yeast, worms and flies

Determinants of cell polarity dictate the behaviour of many cell types during development. Recent work in yeast, worms and flies, reviewed here by Barry Thompson, has combined computer modelling with experimental analysis to reveal the mechanisms that drive the polarisation of such determinants. See the Review on p. 13

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Today’s recommended paper is:

NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage Commitment
Nicola Reynolds et al. (2012)
Cell Stem Cell 10 (5), 583-594

Submitted by Mary Todd Bergman:
“Paul Bertone’s lab at EMBL-EBI discovered a key component of the ‘go’ signal that tells stem cells to commit already and become one type of cell or another. In collaboration with Brian Hendrich at the University of Cambridge, Paul’s group studied differences in gene expression patterns between self-renewing and differentiating stem cells, specifically focusing on the Nucleosome Remodelling and Deacetylation (NuRD) corepressor complex. They found that NuRD directly regulates how pluripotency genes are expressed in stem cells, and that NuRD is required for their exit from pluripotency. They also investigated the binding patterns of the NuRD complex to understand how it regulates its target genes. Combined with transcriptional profiling, a picture emerged of NuRD as a gatekeeper of cell differentiation.”

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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EVODEVO WIKIPAEDIA EDIT-ATHON. Friday December 7th 2012 a the Department of Zoology, South Parks Road, University of Oxford

We are spending a day editing and updating EVODEVO related pages on Wikipaedia. If you would like to join us contact peter.holland@zoo.ox.ac.uk or aziz.aboobaker@zoo.ox.ac.uk

We will start about 10.30 am and two official trainers from Wikimedia UK will joins us at around 11 to help us get started.

(3 votes)

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Today’s recommended paper is:

Bimodal control of Hoxd gene transcription in the spinal cord defines two regulatory subclusters
Patrick Tschopp, Alix J. Christen and Denis Duboule (2012)
Development 139 (5), 929-939

Submitted by Rachael Inglis:
“This is a great example of new results enriching our understanding of a classical developmental phenomenon: the co-linear expression of the Hox gene cluster from anterior to posterior along the spinal cord, which actually turns out to be two sub-clusters that are regulated independently and correspond to the regions of the spinal cord that innervate the forelimb and the hindlimb.”

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:

Polyploidization of glia in neural development links tissue growth to blood–brain barrier integrity
Yingdee Unhavaithaya and Terry L. Orr-Weaver (2012)
Genes & Development 26, 31-36

Submitted by Tohru Yano:
“This paper tell us the link between cell properties and tissue
growth and biological functions.”

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.

(No Ratings Yet)

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Today’s recommended paper is:

The accessible chromatin landscape of the human genome
Robert E. Thurman, Eric Rynes, Richard Humbert, et al. (2012)
Nature 489, 75–82

Submitted by Nishal Patel:
“Whilst humans aren’t exactly a model organism that most developmental biologists work on, the ENCODE project is ground breaking and transcription factors and chromatin accessibility are important in development.”

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.

(3 votes)

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Site upgrade
We now have a “featured topics” bar across the top of the page, which has the same function as these highlight posts: to let you know what happened on the Node recently.

This upgrade also came with author profile page. Do remember to fill out your profile bio, because people can now see this when they click your name on a post you wrote on the Node. Here’s how to do that.

Publishing discussion
A post from last month has started to generate an interesting discussion in the comments section about the future of scientific publishing. Have a look at the comments from scientists and publishers that were left on Jordan Raff’s BiO editorial, and add your own thoughts.

Multimedia conferences
Rachael went to a meeting at the Royal Society about long-range control of gene expression, and Eva attended SpotOn London (about science policy, outreach, and tools). You can read their reviews of the meetings on the Node, but you can also relive both meetings more directly: the Royal Society is making audio of the talks available online, and SpotOn has video of each conference session.

Also on the Node
–BCSB science writing competition
–Sox1 marks neural stem cells in the hippocampus
–new job ads!

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This book review originally appeared in Development. Jennifer Mitchell reviews “Introduction to Genomics” (by Arthur M. Lesk).

Book info:
Introduction to Genomics By Arthur M. Lesk. Oxford University Press (2011) 424 pages ISBN 978-0-19-956435-4 £34.99 (paperback)

The past 20 years has seen a revolution in genomics. From the completion of the human genome in 2003, which took 13 years, we are well on our way to achieving the next benchmark goal of having 1000 human genomes sequenced (The 1000 Genomes Project). This endeavour will provide a deep catalogue of human genetic variation. In addition, and as part of The Genome 10K Project (which aims to sequence the genomes of 10,000 vertebrate species), 2012 saw the initial assembly of the medium ground finch (Geospiza fortis) genome, one of the iconic Galapagos finches described by Charles Darwin. The results of these genome sequencing projects are available through freely accessible public databases, thus accelerating discoveries in diverse fields of biology. With the advent of next-generation sequencing platforms, the time and cost of sequencing have dropped dramatically, making the ability to sequence the human genome in a day for less than $1000 no longer science fiction but rather an event that will happen in the immediate future. The effects of this genomics revolution are widespread, and no field of biology or medicine remains untouched by the changes in sequencing throughput. Furthermore, genomic studies are so commonly highlighted by the media that a working understanding of genomics is increasingly important in undergraduate biology education.

The second edition of Introduction to Genomics by Arthur M. Lesk is a comprehensive introduction to genomics that covers a diversity of topics, from genome sequencing to systems biology approaches used for understanding the metabolome, transcriptome and proteome. This new edition strives to highlight the progress made in genomics due to the increased application of high-throughput sequencing techniques. The text is accessible to undergraduate students; it does a thorough job of providing the basic principles before moving on to more in-depth concepts. The author presents an important discussion of the ethical issues surrounding genome sequencing, including the efforts taken to protect individuals who contribute samples to the large-scale human genome sequencing projects that are currently underway. These issues are presented in a well-balanced and unbiased manner. Importantly, the text is a pleasure to read; detailed colour illustrations are provided throughout, as well as helpful analogies that allow the reader to get to grips with difficult concepts. For example, biological networks are compared to the London Underground map, where the stations are the nodes and the edges the tracks that connect them.

This new edition highlights recent advances in sequencing techniques while still presenting the historical context for the discovery of genomes. Early in the text, the history of the discovery of DNA structure, the need to understand the ‘language of the genome’, and early progress in sequencing techniques are discussed in a narrative manner. Lesk writes, “the sequence of the bases was like a text everyone wanted to read, not only was the text in an unknown language, but there were not even any examples of the language, because the sequences were unknown”, thus framing the importance of early DNA sequencing efforts in ultimately decoding the human genome. This leads into the development of Sanger sequencing, a method developed by Frederick Sanger, and the sequencing of the 5386 bp ΦX174 bacteriophage genome, the first completed DNA genome sequence. Following on from this is the adaptation of Sanger sequencing to automated DNA sequencing using fluorescent tags and next-generation high-throughput sequencing techniques. As in the rest of the book, colour illustrations are used to great effect to explain the techniques and to provide examples of data output. These examples of data output are increasingly important, as so few students today will ever perform a Sanger sequencing reaction and see how the individual base-terminated chains resolved on the gel are composed into a sequence. So, although this technique has been replaced with higher throughput variations, the visual understanding of the sequencing process provided by inspecting a Sanger sequencing gel remains unmatched.

At the end of each chapter, selected additional reading is provided with problems that test the concepts discussed. The problems posed range from testing the basic understanding of the material to more thought-provoking questions that will allow students to test and deepen their understanding of the material. Of special note are the ‘weblem’ problems, which require the use of online genomics resources. These encourage students to develop a proficiency in the use of these resources, many of which are linked to the text through the publisher’s website. A ‘guided tour’ of genomics websites provides a list of websites with short descriptions and links to instructions or tutorials where available; however, this is merely a teaser that will hopefully push young scientists to explore more thoroughly the information that is available online to the scientific community.

Although the second edition is updated with expanded content, the information on data gathered from next-generation sequencing projects is rather limited. However, as the author points out, this is a moving target with advances made weekly, and it is therefore difficult to ensure that the material is up to date in a text of this type. Even with this in mind, I found that the section on deep sequencing of transcriptomes and functional genomics could have been expanded upon; there is a huge wealth of genome-wide functional genomics data for human, mouse, fly and worm genomes generated by the ENCODE and modENCODE projects, which are only briefly mentioned (Gerstein et al., 2010; modENCODE Consortium, 2010; ENCODE Project Consortium, 2011). These data are easily accessible through online browsers (UCSC Genome Browser, modENCODE GBrowse), massively accelerating the discovery of new genes, non-coding RNAs and regulatory elements such as enhancers and insulators. With the focus on students exploring genomics data on the web, these resources could have been better highlighted.

Given the widespread impact that sequenced genomes have on research, medicine and the general public, an introductory text such as this is an important resource. Introduction to Genomics is beautifully illustrated, supported by end of chapter and additional online resources, and written in an eloquent and readable style. Beyond focusing on genome sequencing and comparative genomics, a good deal of the text is concerned with transcripts, proteins and proteomics. However, there is minimal mention of transcriptional regulatory regions of the genome. I would have liked to see more emphasis given to transcription factor binding in the genome, epigenetic modifications and chromatin features, which are proving invaluable in identifying intergenic regulatory regions. Given the observation that disease-linked single-nucleotide polymorphisms are more often found in non-coding than in coding regions (Manolio, 2010), understanding how regulatory regions function is crucial in decoding the human genome and understanding predisposition to disease. Nonetheless, Introduction to Genomics is a comprehensive textbook that provides a solid introduction to the study of genomes and will be a great resource to undergraduate students with a background in molecular biology. The text also provides a useful resource for graduate students in other fields who want to make use of the growing number of online genomics resources.

(1 votes)

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We recently asked you what your favourite papers of 2012 were. From December 1 to 24, you’ll be able to see 24 of these papers behind the virtual doors of our advent calendar. Come back each day, click the calendar in the sidebar, and find out what your colleagues – from students to lab heads – have recommended.

New papers will go up each day at 8AM GMT.

We have contacted the publishers of the recommended papers that were behind a pay wall, and are happy to report that they’ve agreed to give you free access to the papers on at least the day they are featured. Many thanks to all publishers!

(3 votes)

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