Biology has been revolutionized by the impact of physical forces on cell behaviour as in vivo cells are exposed to a combination of biochemical and physical cues that regulate their function. These revolutions have generated in biologists and physicists a need for new tools to analyze cellular structures. In fact, this was precisely the motivation of the “Quantissue Symposium” organised by Hernán López-Scheir and that was held in the CRG the 13-15^th February 2012 in Barcelona (Spain).

The main benefits for attendees have been the gained insights into the quantitative description and analysis of biological processes. This symposium provided also a forum for scientists working at the interface of physical and biological science to discuss technologies, processes and ideas. We want to share with all of you the hot topics in this field and hope that this is also useful for those that were not able to attend!

Mechanical cell forces (pushes, pulls, tensions, compressions) are important regulators of cell development and behaviour because cells use tension to stabilize their structure. But tension, understood as the sum of biochemical stimulus and physical cues, not only gives cells their shape, but also helps to regulate their biochemistry. To understand this complexity of biological systems in the context of development and disease, modelling and biological computer simulation were addressed (we would like to highlight Xavier Treapat’s and James A. Glazier’s talks) and appeared as the common issue among the meeting talks as a powerful approach to resolve and quantify, at the subcellular and even molecular levels, the spatiotemporal dynamics of molecules and processes inside cells.

Alfonso Martínez Arias’ main interest is to understand the molecular basis of embryonic stem cell pluripotency. He spoke about the “sensitivity” inherent to this cellular state to transcriptional noise associated with the transcription factor Nanog.

During lunchtime we have enjoyed a delicious meal in an ideal environment (in front of the Mediterranean sea!) creating an atmosphere that fosters dialogue and debate on thoughts and ideas. Furthermore, the “Quantissue Symposium” offered the alternative to present scientific work in a poster format. We believe this is a very interesting option that has two-way information exchange: the audience is more likely to question and there is a real opportunity for detailed discussion. In addition, we must mention that we were impressed about the quality of the work presented in this design!

We had the opportunity after the Symposium to attend the complementary Workshop:
“Tracking across scales: from single molecules to cells” that was coordinated by Richard Adams, Carl-Philipp Heisenberg, and Marcos González-Gaitán. It was the perfect moment to learn in a more exclusive but also practical environment the latest techniques in the biophysical field.

Our “Quantissue Symposium” home message: Apart from enhancing synergies between different groups, the symposium emphasized that cells are the basic structural and functional unit of all known living organisms, whereas cellular forces and transcriptional noise are responsible for tissue architecture and shaping the embryo!

(6 votes)

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Last week, I attended the GSA Drosophila Genetics Meeting in Chicago. You’ll hear more about the main part of the meeting later, or you can check out the Storify of the tweets from the conference. In this post I wanted to specifically highlight one of the lunch sessions.

The GSA had invited Jennifer Zeitzer, Director of Legislative Relations at FASEB, to talk about science advocacy over lunch. There were about a dozen scientists in the room, but what she talked about is interesting to quite a number of people, so I’ll try to recap some of the main points she made.

The talk was aimed at American researchers, but much of the message is applicable to other countries: Politicians know very little about science, they never meet scientists, and there is always a limited amount of money to be distributed. If you want these things to change, you can, and should, step up. Here are a few of the points Jennifer discussed in her talk:

Be vocal
One of the main points Jennifer made, was that scientists need to be more vocal. Small organizations that make a lot of noise always get a lot of attention (she gave the Tea Party as example) but scientists barely make themselves seen or heard to politicians. She emphasized the importance of individuals fighting for science policies and science funding. Even though there are various professional organizations fighting on researchers’ behalves, it makes a much bigger impression if scientists themselves come up and speak to politicians.

Have a clear message
Your message should be clear and very specific. Ask for specific amounts, or for support for specific projects. Be realistic in terms of what you can expect, and be prepared to address suggested trade-offs.

Contact politicians and build relationships
In countries like the US and UK (and others with similar voting systems) you will have a local elected official or member of parliament whom you can email or make an appointment with. They are representing you and the other people living in your area, and they really want to hear from you.

If you email, make sure to only include one issue per message, and be very clear. Several politicians are also on Twitter. Some have aides that handle those media for them, while others do it themselves.

Because so few politicians know any scientists personally, they will be happy to meet you, and may even want to pick your brain in the future. Even PhD students and postdocs, who may feel they’re not senior enough, are incredibly useful contacts for politicians to have. To them, you ARE a scientist. You’re using the funding and the facilities and doing the work! And if they ask you something you don’t know, you can always tell them that you will ask someone or look it up.

If you don’t know any politicians personally, keep an eye out for possible connections, via alumni organization, for example.

Generate public awareness
Another way to be involved in science advocacy is simply by doing anything that increases the public awareness of the impact of research in your community. You can give talks at schools or community groups, invite elected officials to visit your lab, or write a letter to the local paper.

The FASEB office of public affairs (where Jennifer works) is on Twitter as @FASEBopa and their website also has a handy list of advocacy resources for scientists.

To add to these notes of the advocacy lunch, I wanted to share a real-world case of science advocacy that involved many of the examples in this talk. In 2010, a group of scientists in the UK managed to stop a proposed cut in science funding. The Science is Vital campaign was started by individuals (not an organization), made extensive use of contacts to reach politicians and the public, involved scientists rallying at parliament and people meeting politicians for conversations, and had a very clear and specific message. Find out more on their site.
(Their follow-up campaign, on science careers, was covered on the Node.)

(4 votes)

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The progress of stem cell research depends on the ability to grow stem cells in culture.  Embryonic stem (ES) cells from some organisms, such as humans, have proven difficult to culture.  While it is known that there are differences in early development between even closely-related species, understanding where these differences begin will help biologists understand how to culture other ES cells, and will contribute to our understanding of pre-implantation development.  A recent paper in Development helps sort out some of these nuances.

Before implantation, an early mammalian embryo has already formed three distinct cell lineages.  First, the trophectoderm lineage is segregated from cells of the inner cell mass, and will contribute to the placenta.  Within the inner cell mass, the hypoblast precursors, which contribute to the yolk sac, are segregated from the epiblast precursors, which will become the actual embryo.  In mice, the segregation of hypoblast and epiblast lineages is regulated by FGF/MAP kinase signaling, and inhibition of MEK signaling prevents ES cells from differentiating.  Despite this knowledge of mouse early development and embryonic stem cells, human ES cells remain difficult to culture.  Kuijk and colleagues recently published work describing the differences in the signaling involved in hypoblast and epiblast lineage segregation in both human and bovine cultured embryos.  Specifically, bovine embryos with stimulated FGF and heparin levels had only hypoblast cells but no epiblast cells, and MEK inhibition resulted in more epiblast cells and fewer hypoblast cells.  That hypoblast cells were not completely ablated after MEK inhibition indicates that other signaling is important in hypoblast differentiation.  Interestingly, MEK inhibition of early human embryos did not affect the numbers of hypoblast and epiblast cells.  Images above are of an early human embryo, immunostained for NANOG (to mark early epiblast cells) and GATA4/6 (to mark early hypoblast cells).  At this point in development (day 6), the epiblast precursors are surrounded by hypoblast precursors, indicating that the physical separation of the cell lineages has occurred.

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

Kuijk, E., van Tol, L., Van de Velde, H., Wubbolts, R., Welling, M., Geijsen, N., & Roelen, B. (2012). The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos Development, 139 (5), 871-882 DOI: 10.1242/dev.071688

(2 votes)

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The Grammy Awards are held every year to celebrate the best of the music industry, however, they seem to miss one crucial catergory – the Science Parody. The Biotechnique’s website has remedied that by having it’s own Lab Grammys for the past two years.

This year’s Grammy was won by Mark Grabiner and his colleagues from the department of Molecular and Cell Biology at Berkeley for a brilliant parody of LCD Soundsystem called “Grad School, I Love You (But You’re Bringing Me Down)”.

Last year’s Science Parody Grammy was won by the Zheng Lab for Bad Project.

The full list of nominees for the 2012 Lab Grammys can be found here.

(6 votes)

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The Wellcome Trust Centre for Stem Cell Research provides outstanding scientists with the opportunity and resources to undertake ground-breaking research into the fundamental properties of mammalian stem cells.

Postdoctoral Research Associate in Transcriptional control of embryonic stem cell differentiation PS14181

Salary £ 27,578 – £35,938

Applications are invited for a postdoctoral position to investigate the molecular control of embryonic stem cell lineage commitment and differentiation. As part of the European Commission 7thFramework Programme Project “4DCellFate,” you will spearhead the lab’s effort to elucidate how cells use the biochemical complexity of transcriptional silencing complexes to derive cellular diversity from pluripotency.

For this position demonstrated experience in the analysis of transcriptional and developmental mechanisms will be required. The candidate is expected to have considerable expertise in molecular biological and biochemical techniques and in mammalian embryonic stem cell culture and manipulation. Previous experience in early mammalian embryogenesis and gene targeting is highly desired. The position will be in the Transcriptional Control of Stem Cell Fate Group and is available immediately. The funds for this post are available for 2 years in the first instance.

You should have been awarded a PhD degree or equivalent and have substantial laboratory experience.
Informal enquiries are welcome via email to: Dr Brian Hendrich Brian.Hendrich@cscr.cam.ac.uk or to cscrjobs@cscr.cam.ac.uk
To apply, please visit our vacancies webpage: http://www.cscr.cam.ac.uk/careers-study/vacancies/
Applications must be submitted by 17:00 on April 16th 2012.
Interviews will be held week commencing 23rd April 2012
If you have not been invited for interview by the shortlisting deadline on 19th April 2012, you have not been successful on this occasion.

05 March 2012 – 16th April 2012

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(This interview originally appeared in Development.)

Angela Nieto is Full Professor at the Instituto de Neurociencias (CSIC-UMH) in Alicante, Spain, and Head of the institute’s Developmental Neurobiology Unit. She is also the current president of the Spanish Society for Developmental Biology (Sociedad Española de Biología del Desarollo, SEBD). We interviewed her to talk about the plans of the SEBD for the coming years.

What research topics are you working on?

We have been working on the mechanisms that drive cell movements early in development. More than 20 years ago we started to work on the Snail family of transcription factors and found that, in vertebrates, Snail factors are very important for the triggering of the epithelial-to-mesenchymal transition (EMT) in the embryo. Therefore, Snail factors are necessary for cell delamination at the primitive streak and at the neural crest, as well as in other tissues. Essentially, the EMT has kept us very busy for many years now. Over the years we have extended our analysis to not only study the EMT during embryonic development, but also in pathology – particularly in tumour progression and in other diseases that involve the EMT. We also extended our research into the role of Snail to EMT-independent processes, such as bone growth and homeostasis, and started investigating some other EMT inducers.

You’re the president of the Spanish Society for Developmental Biology. How long have you held this position?

I’ve been president for a year now, and it has been quite a busy year, because we are revitalizing the society at the moment. For example, we have written new statutes to accommodate the society to new regulations.

How was the SEBD originally formed?

The society was initiated in 1994, in association with the International Journal of Developmental Biology (IJDB). Juan Aréchaga, of the University of the Basque Country, is the Editor in Chief of the IJDB and put a lot of effort into the journal. At the same time it was important to have Antonio Garcia-Bellido, one of the main figures in developmental biology in Spain, working together with Juan Aréchaga to create the society. At the moment, the links with the journal are still tight, but the society has become more independent.

How often does the SEBD organize meetings for its members?

The first meeting was held in 1996, in Bilbao. From then on we’ve had meetings every 2 years, and we will continue to do that. We’re also interested in interacting more with other developmental biology societies, so we often organize joint meetings. We have done this already with the British, Portuguese and French societies for developmental biology, and at our next meeting in November – again held in association with the Portuguese society – we will have the North American Society for Developmental Biology as an invited guest. We are very close to the Portuguese society and have plans for a long-term association, so that we can perhaps have meetings every year: one year in Spain and the next year in Portugal.

What would you like to see the society achieve in the near future?

We want to promote the various activities of the society. Notably, we are trying to increase the interactions among the members and strengthen our ties with other European societies. But at the same time we have two additional aims. One is to encourage young scientists to be interested in developmental biology. The second is to increase the visibility of the SEBD and of scientific research in general to Spanish society. In Spain, there is not much of a tradition of explaining science to lay people. However, we know that people in Spain are extremely interested in science and scientists. To give you an idea, some recent statistics showed that when you ask laypeople their opinion on different professions, scientists come out very high. The Spanish public really appreciates what scientists do and they trust scientists very much. This is very nice, and it serves as a strong message that we have to communicate the research we do, and that we should be able to provide the public with an informed opinion on several issues related to developmental biology, including those linked to bioethical issues. As a scientific society, we may have to work together with the mass media. That is something that I think hasn’t been done properly in the past, but which the public is actually asking us to do.

What are the current challenges for researchers in Spain?

Undoubtedly, one of the challenges is the economic crisis, which not only affects Spanish science, but also science in the rest of Europe and all over the world. At the start of this year, we received bad news, as the Ministry of Science and Innovation has been discontinued, and investment in research and development will be reduced in Spain, which is very disappointing. Securing funds for research may also be related to scientific outreach and keeping the public informed: if society believes that investing in research is crucial, then it will be easier to convince politicians that research should be protected and that cutting down the budget for science means cutting down our progress and our future.

How can Spanish developmental biologists play a role in this?

It is now easier than ever to promote translational research and, as developmental biologists, many of us have connections with biomedicine. But we have to firmly support investment in basic research. We have to convey the message to the public that we really need to know the physiology of the biological processes before we can design intelligent strategies for therapies.

Does the SEBD have any concrete plans for providing public outreach?

In this first year of the new society committee we’ve been busy trying to generate all the instruments that we actually need to carry out our activities. We have a new webpage (www.sebd.es) and we’re preparing a lot of different activities to promote visibility and interactions – those will be launched this year. We would like to promote not just developmental biology but scientific research in general. Not only at universities, to try to attract PhD students, but also by going to schools to show kids how much fun it is to work in science. Scientific research takes a lot of effort, and although sometimes it’s disappointing because experiments don’t always work, it is very exciting and it is always different. That is the message we hope to pass on during school visits: science is fun and, very importantly, essential for our future.

(2 votes)

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Here are the research highlights from the current issue of Development:

miR-125 seals hESC neural fate

MicroRNAs, small non-coding RNAs, have recently emerged as key regulators of embryonic development. In particular, they can coordinate cell fate determination by blocking alternative cell fate choices. Here (p. 1247), Alexandra Benchoua and colleagues report that the microRNA miR-125 contributes to the neural specification of pluripotent human embryonic stem cells (hESCs). By using a culture system that promotes hESC neuralization, the researchers show that miR-125 is expressed in a time window compatible with a role in neural commitment in vitro. They show that miR-125 promotes the conversion of pluripotent cells into SOX1-positive neural precursors by, at least in part, blocking the expression of SMAD4, a key regulator of pluripotent stem cell lineage commitment that promotes non-neural cell fates. Finally, the researchers show that expression of miR-125 is responsive to the level of TGFβ-like molecules. Together, these results identify a central role for miR-125 in the irreversible neural lineage commitment of pluripotent stem cells in response to external stimuli.

GLE1: keeping neural precursors alive

Lethal congenital contracture syndrome 1 (LCCS1) is a prenatally fatal, autosomal recessive human disorder. Affected foetuses have multiple defects, including limb deformities (contractures), loss of voluntary muscle movement and a distinct neuropathology. Mutations in GLE1, which encodes a protein involved in mRNA export and translation, have been implicated in LCCS1 and, on p. 1316, Susan Wente and co-workers investigate the link between Gle1 function and LCCS1 pathology using zebrafish as a model system. They report that disruption of Gle1 function produces phenotypes in zebrafish embryos that parallel those of human LCCS1 foetuses, including a reduction of motoneurons and aberrant arborization of motor axons. Surprisingly, the researchers report, apoptosis of neural precursors, rather than degeneration of differentiated neurons, as previously suggested, causes the motoneuron deficiency. The researchers propose, therefore, that rapidly dividing cells, including organ precursors in both neuronal and non-neuronal tissue, have a high demand for Gle1 activity, and that apoptosis of these precursors because of Gle1 deficiency produces the pleiotropic abnormalities seen in LCCS1 foetuses.

Separating karrikin and strigolactone effects

Karrikins are smoke-derived butenolides that, by stimulating seed germination and enhancing seed responses to light, allow plants to exploit reduced competition for light, water and nutrients after wildfires. By contrast, strigolactones are plant-derived butenolides that regulate shoot and root architecture. In Arabidopsis, responses to both classes of molecule require the F-box protein MAX2, so how are the physiologically distinct responses to karrikins and strigolactones achieved? Here, Mark Waters and colleagues suggest that the answer to this puzzle lies with evolutionary specialization within the DWARF14 superfamily of α/β hydrolases (see p. 1285). In rice, strigolactone-dependent inhibition of shoot branching requires DWARF14. The researchers show that, in Arabidopsis, the DWARF14 orthologue AtD14 is necessary for normal strigolactone responses, whereas the AtD14 paralogue KAI2 is required for karrikin responses. Notably, the expression patterns of AtD14 and KAI2 are consistent with the plant’s capacity to respond to specific growth regulators at different developmental stages. Thus, AtD14 and KAI2 define proteins that permit the separate regulation of strigolactone and karrikin signalling by MAX2.

Foxj1: Not(o) enough for node function

During embryonic patterning in amniotes, cilia in the node generate a leftward flow of extra-embryonic fluid that establishes left-right asymmetry. Now, on p. 1276, Achim Gossler and co-workers report that Noto and Foxj1 (two key transcription factors that are expressed in the node) differentially regulate mouse node formation, nodal ciliogenesis and cilia positioning. Noto, which controls node morphogenesis, nodal ciliogenesis and left-right asymmetry in mice, acts upstream of Foxj1 but the role of Foxj1 in nodal ciliogenesis is unclear. To address this issue, the researchers analyse mouse embryos deficient for Foxj1 and embryos in which the Foxj1-coding sequence replaces the Noto-coding sequence. Foxj1 expressed from the Noto locus is functional and restores the formation of motile nodal cilia. However, in the absence of functional Noto, Foxj1 is insufficient for the correct positioning of these cilia and cannot restore normal node morphology. Thus, the researchers conclude, Noto regulates nodal ciliogenesis through Foxj1 but regulates node morphogenesis and cilia localization independently of Foxj1.

Engrailed 1 shapes the skull

Bones in the vertebrate skull are connected by cranial sutures: flexible fibrous joints that are essential for normal postnatal brain growth. The coronal suture separates the parietal and frontal bones, which are derived from cephalic paraxial mesoderm (Mes) cells and neural crest (NeuC) mesenchyme, respectively. But where do the mesenchymal precursors that generate the coronal suture come from? Ron Deckelbaum, Cynthia Loomis and colleagues (see p. 1346) use genetic fate mapping to show that, in mice, these precursors originate from hedgehog-responsive Mes cells that migrate into a supraorbital domain to establish a lineage boundary with NeuC mesenchyme. Importantly, the researchers show that the transcription factor Engrailed 1 (En1) regulates cell movement and NeuC/Mes lineage boundary positioning during coronal suture formation, and also prevents premature osteogenic conversion of the sutural mesenchyme by controlling the level of fibroblast growth factor receptor 2. Further investigation of these molecular mechanisms could lead to cell-based therapies for craniosynostosis (premature suture closure), which can cause craniofacial deformities and impaired brain development.

Well wrapped: vimentin regulates myelination

Myelination of peripheral nerves, which is essential for the rapid and efficient propagation of electrical messages along axons, has to be carefully controlled during development. However, the molecular mechanisms that determine myelin sheath thickness are only partly understood. Here (p. 1359), Stefano Carlo Previtali and colleagues report that the intermediate filament protein vimentin negatively regulates peripheral nerve myelination. Vimentin is highly expressed in Schwann cells and neurons during embryonic development and during nerve regeneration. The researchers show that loss of neuronal vimentin results in peripheral nerve hypermyelination in transgenic mice and in a myelinating co-culture system. This increased myelin sheath thickness occurs, they report, due to an increase in the levels of axonal neuregulin1 (NRG1) type III, a key regulator of myelin formation in peripheral nerves. Finally, they show that vimentin acts synergistically with the protease TACE to regulate NRG1 type III levels. Together, these results provide new insights into peripheral nerve myelination and identify potential targets for the treatment of peripheral neuropathies.

Plus…

Fluid flows and forces in development: functions, features and biophysical principles

Cells are subjected to various forces during morphogenesis, including those resulting from microscopic fluid flows. Here, Julien Vermot and colleagues review the biomechanical features and the physiological functions of biological fluid flows during development. See the Review article on p. 1229.

(1 votes)

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I recently saw a documentary about graduate students called Naturally Obsessed: The Making of a Scientist (available to watch here). It’s hour long movie follows several PhD students from Lawrence Shapiro’s lab in Columbia, NY, for 3 years as they attempt to crystallise and work out the structure of AMPK, a cellular master regulator involved in several metabolic pathways such as glucose regulation and lipogenesis.

The three PhD students the film focuses on are Rob (below right with Lawrence), Kilpatrick (Kil) and Gabrielle. Rob is given the most screen time. He is a two-time university drop-out and navy veteran on his last chance to get a PhD after being kicked out of another lab for being disruptive. Kil is desperate to finish before he turns 30 and is also under pressure to get a job from his fiancée. Gabrielle is a former technician who’s story isn’t dwelt upon as much as the others and she is seen to be struggling with being an independent researcher.

Lawrence Shapiro comes out as a great mentor, a zen-like father figure ready to offer advice to his students. He sees a PhD as more of an apprenticeship rather than a job (he makes a really nice comparison between scientists and violinists around 12 minutes in).

I always thought a reality show about life in the lab would be a great way to show the public how the world of science works rather than the shiny lab coats and 20 second PCR reactions shown on TV. I’m glad Richard and Carole Rifkind took the initiative to make this. The film is great in that it not only highlights the curiosity that motivates scientists, it also deals with the ups of experiments that worked and the downs of those that failed as well as the ever present threat of being scooped. It’s also really well made, quite funny and easy for the general public to understand, so next time someone asks you what working in a lab is like, show them this movie!

On a more light-hearted note, here are a couple of viral video came out recently that many Node readers might identify with as well – “Sh!t Graduate Students Say” and “Sh!t Scientists Say” – enjoy!

(4 votes)

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The Metazoa, our corner of the great assemblage of life, is a curious and fascinating topic, but one that is relatively obscure in these days when a great many of the scientists studying animals are concerned with them as biomedical model systems. ‘The Animal Kingdom: A Very Short Introduction’ goes a long way to illuminating this relative obscurity, and is likely to become an excellent first point of call for undergraduate and graduate students of evolutionary-developmental biology (‘evo-devo’). It will also make for a fascinating read for biomedical scientists who are fed up of their evolutionarily-minded colleagues lecturing them about how fascinating velvet worms (Phylum: Onycophora) are.

Animals come in a huge variety of sizes and forms and their interrelationships have been the subject of often very heated debate since the 19^th century. The coming of the age of molecular biology has revolutionised these debates by enabling zoologists to infer evolutionary relationships by comparing DNA and protein sequences; they no longer have to rely on the vagaries of morphological comparisons. This has lead to a number of significant revisions. Previously well-established groups such as ‘Articulata’, which united segmented invertebrates such as insects and earthworms, have been shown to be artefacts of convergent evolution or widespread character loss. As with all revolutions, there have been dissenting voices (tales of warring academics who wouldn’t set foot in the same lecture theatre as one another are not unknown). However, as the sophistication of molecular phylogenetic techniques has advanced, and datasets have grown exponentially owing to the power of next-generation sequencing (people talk only of phylogenomics these days), a consensus of the animal phylogeny has been arrived at. Of course, the arrangement of many groups is still unresolved and problems remain, but the broad brush strokes of animal evolution are agreed upon: the family tree of the 30-odd animal phyla (Prof. Holland recognises 33 in his book) is largely established. As a guide not only to the diversity of animals, but also to their evolution ‘The Animal Kingdom: A Very Short Introduction’ thus comes at a very timely juncture.

Prof. Holland’s book takes readers on a tour of the Metazoa using an evolutionary framework. After discussing the issue of what an animal is, and then addressing the much thornier one of how to organise our thinking about them phylogenetically, the book discusses each of the prominent groups. Firstly dealing with the basal animals that do not possess bilateral symmetry (sponges, jellyfish and the like), and then taking each major group of Bilateria in turn, the book provides a lucidly written guide to the diversity of animal form and how it is generated during development. As such, it is an excellent introductory evo-devo text.

For old hands, the description of the molecular revolution of the 1980s and the discovery of the ‘developmental toolkit’ is particularly entertaining. Capturing the excitement at the discovery of the homeobox sequence is a difficult thing to do in 2012, when it is possible to sequence a human genome in 15 minutes. But it’s worth the money on its own. I heartily recommend it.

(8 votes)

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Progress in understanding how cells interpret their genome has gathered significant momentum in recent years. Of course, the (now historical) catalyst to this was the entry into the genomic age, marked most obviously by the sequencing of the human genome. However, it is the genome-wide application of novel techniques for understanding how this genome is interpreted that has begun to unlock its secrets. In 2007, the international ENCODE consortium reported its initial attempts to annotate, in exhaustive detail, the best understood 1% of the human genome (ENCODE Project Consortium, 2007). The application of such genome-wide efforts to the leading invertebrate model species, Caenorhabditis elegans and Drosophila melanogaster, was published earlier this year (modENCODE Consortium, 2010a, b).

Much has come out of these gargantuan efforts, but one of the most prominent conclusions has been that general speaking, the genome is pervasively transcribed. A whole universe of RNA molecules exist inside cells, and while the extent to which they are functional remains a subject of much debate, it is clear that understanding this universe will yield fundamental insights into cellular, and developmental biology. Against this backdrop, recent work outlining the positive gene regulatory roles of particular populations of non-coding RNAs (ncRNAs) constitute hugely important discoveries. They build upon a landmark study, published in 2009 (Guttman et al. 2009), that for the first time systematically identified a population (~1600) of long multi-exonic ncRNAs in four murine cell lines. Correlative analysis with existing and novel expression datasets suggested putative functions for numerous distinct sets of lincRNAs. At the other end of the size scale, short (<2kb) RNAs, termed enhancer RNAs (eRNAs) have recently been shown to be transcribed from active enhancers in a neuronal cell culture system (Kim et al. 2010). Both of these findings give meaning to the pervasive transcription observed in the ENCODE and MODENCODE studies, but they don’t address the function of such RNA species. Do the RNAs themselves act to govern transcription or cell behaviour, or is it merely the act of transcribing them that is important, perhaps to re-model the local chromatin environment?

This conundrum has begun to be resolved, at least for longer species of ncRNAs, in the last two years. Two papers, one using differentiated cell lines (Ørom et al. 2010), and one in reference to ES cell biology, again from Eric Lander’s group (Guttman et al. 2011), have unequivocally demonstrated the functional importance of ncRNA species themselves. In the first, after using the ENCODE annotations to identify a population of 3019 putative long ncRNAs, a combination of reporter siRNA-mediated knockdown and expression analysis was able to show that the knockdown of particular ncRNAs were in seven cases able to decrease the expression of neighbouring genes, implicating the RNAs as positive regulators of a diversity of developmental processes. In the second study, building on their data set of lincRNAs (Guttman et al. 2009), the authors have demonstrated using short hairpin RNAs that dozens of lincRNAs are fundamental players in promoting and controlling the gene regulatory networks that govern both pluripotency, and differentiation into a range of different lineages. Further, they show that many lincRNAs specifically interact with chromatin regulatory proteins, and present a model that fully integrates ncRNAs into gene regulatory programmes that control cell fate.

Thus, extensive evidence now exists that implicates ncRNAs both in cis and in trans as fundamental controllers of all aspects of cell biology. The implications of such work will be felt across cell and developmental biology. As important as the findings themselves though, has been the illustration that integrating a diversity of epigenetic, comparative genomic and next generation sequencing approaches is capable of revolutionizing our understanding of how phenotype derives from genotype. The stage is set for application of these approaches over the coming years to develop from cell lines to developmental contexts. ncRNAs of all flavours are likely to be of fundamental, and as yet underappreciated, importance.

References

ENCODE Project Consortium (2007) Nature 447: 799-816.

Guttman M et al. (2009) Nature 458: 223 – 227.

Guttman M et al. (2011) Nature 477: 295 – 300.

Kim TK et al. (2010) Nature 465: 182 – 187.

modENCODE Consortium (2010a) Science 330: 1775-1787.

modENCODE Consortium (2010b) Science 330: 1787-1797.

Ørom UA et al. (2010) Cell 143: 46-58.

(5 votes)

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