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

Nr5a receptors reset EpiSC pluripotency

Rodent embryonic stem (ES) cells that are derived from blastocysts self-renew without mitogenic growth factors and robustly colonize chimaeras, whereas egg cylinder-derived stem cells (EpiSCs) require fibroblast growth factor and contribute poorly to chimaeras. Nevertheless, expression of a single reprogramming gene, such as Klf4 or Nanog, can return EpiSCs to a molecular and developmental pluripotent ‘ground state’. Now, on p. 3185, Ge Guo and Austin Smith use a genome-wide genetic screen to identify other molecules that can reprogramme EpiSCs. By using piggyBac transposition to randomly activate endogenous gene expression in mouse EpiSCs and by selecting for undifferentiated colonies in the absence of growth factors, the researchers unexpectedly identify the Nr5a nuclear receptors as potent inducers of ground state pluripotency. Intriguingly, they also show that, unlike previously identified reprogramming factors, Nr5a receptors do not play a role in ES cell renewal. Together, these results highlight the usefulness of EpiSC conversion (in defined culture) as an experimental system for studying molecular reprogramming.

EGFR-Notch signalling makes (proneural) waves

During neurogenesis in the Drosophila optic lobe, a wave of differentiation that converts neuroepithelial cells into neuroblasts sweeps across the neuroepithelial sheet in a medial to lateral direction. This differentiation wave is preceded by the ‘proneural wave’: the transient expression of the proneural gene lethal of scute [l(1)sc]. Now, Tetsuya Tabata and colleagues report that EGFR and Notch signalling play pivotal and coordinated roles in proneural wave progression in the Drosophila optic lobe (see p. 3193). They show that EGFR signalling is activated in neuroepithelial cells and induces l(1)sc expression. Transient, spatially restricted expression of Rhomboid regulates EGFR, they report, and Rhomboid expression is regulated by the EGFR signal, a feedback loop that moves the proneural wave laterally. The researchers also report that Notch signalling, which prolongs the proneural state, is regulated both by itself and by EGFR signalling. Based on these results, the researchers propose that coordinated sequential EGFR and Notch signalling regulates proneural wave progression, which, in turn, induces neuroblast formation in a precisely ordered manner.

Hand2 on heart: promoting cardiac fusion

The embryonic heart tube forms from bilateral groups of cardiomyocytes that move towards the embryonic midline where they merge. The transcription factor Hand2 is essential for this ‘cardiac fusion’ but its downstream effectors are unknown. By studying zebrafish heart development, Deborah Yelon and colleagues now identify Fibronectin as a component of the Hand2 pathway that mediates cardiac morphogenesis (see p. 3215). By performing transplantation experiments between wild-type and hand2 mutant embryos, the researchers show that hand2 regulates cardiac fusion by altering the environment through which the cardiomyocytes migrate. Next, they show that fibronectin 1 (fn1) expression is increased in hand2 mutant embryos. Finally, they report that reduction of fn1 function rescues cardiac fusion in hand2 mutant embryos but not the apicobasal polarity defect that is also seen in these embryos. Thus, the Hand2 pathway regulates cardiac morphogenesis by establishing an appropriate environment for cardiac fusion by limiting Fibronectin function but it establishes the apicobasal polarity that is needed for heart tube extension through another, unidentified, effector.

Wise up to Wnt’s role in tooth development

The number, size and shape of mammalian teeth vary widely – just compare a person’s smile with a dog’s ‘smile’. But what controls the patterning of dentition? Mutations in Wise (Sostdc1), which encodes an inhibitor of Lrp5- and Lrp6-dependent Wnt signalling, cause patterning defects in tooth development in mice. Now, by investigating the pathways modulated by Wise, Robb Krumlauf and co-workers show that crosstalk between Wnt and other signalling pathways controls mouse tooth development (see p. 3221). The researchers use genetic experiments to reveal that Wise suppresses the survival of vestigial tooth buds in the normally toothless region between the incisors and molars by inhibiting Lrp5- and Lrp6-dependent Wnt signalling. They also identify the Fgf and Shh signalling pathways as major downstream targets of Wise-regulated Wnt signalling, and show that Shh acts as a negative-feedback regulator of Wnt signalling. Thus, the researchers suggest, variations in the expression of signalling modulators such as Wise could underlie the evolutionary diversity in mammalian dentition.

Del1-ving into forebrain development

During early embryogenesis, morphogen gradients specify the neural plate along the anterior-posterior axis. Canonical Wnt signalling causes the posteriorization of neural tissues. Consequently, Wnt signal attenuation in the embryo’s anterior region is required for the determination of the head region; but how is this achieved? On p. 3293, Hidehiko Inomata, Yoshiki Sasai and co-workers reveal that modulation of canonical Wnt signalling by the extracellular matrix protein Del1 (Developmental endothelial locus-1) is essential for forebrain development in Xenopus embryos. Del1 overexpression expands the forebrain domain, the researchers report, whereas Del1 functional inhibition represses forebrain development. They show that Del1 function in neural plate patterning is mediated mainly by inhibition of canonical Wnt signalling downstream of β-catenin. Notably, however, Del1 inhibition of canonical Wnt signalling involves the Ror2 (receptor tyrosine kinase-like orphan receptor 2) pathway, which is implicated in non-canonical Wnt signalling. These data suggest that Del1 promotes forebrain development by creating a local environment that attenuates the cellular response to Wnt signals via a unique pathway.

Extracellular signal PARtners asymmetric division

Asymmetric cell divisions generate cell diversity during development, and the orientation of the axis of these divisions determines the future position of differentiated cells. But is the asymmetrical localization of the polarity (PAR) proteins that control asymmetric cell division regulated by extracellular or intracellular signals? On p. 3337, Yukinobu Arata and colleagues answer this controversial question. In C. elegans embryos, the P0 zygote and the P1, P2 and P3 germline cells undergo a series of asymmetric divisions. By examining the development of these germline cells in vitro, the researchers show that, although PAR-2 is distributed asymmetrically in P2 and P3 cells in the absence of extracellular signals, the orientation of PAR-2 localization in these cells depends on their contact with endodermal precursor cells. Other experiments indicate that the endodermal precursor cells control the orientation of PAR-2 localization by extracellular signalling via the MES1/SRC1 pathway. The researchers propose, therefore, that Src is an evolutionarily conserved molecular link that coordinates extrinsic cues with PAR protein localization during asymmetric cell divisions.

Plus…

KNOX genes: versatile regulators of plant development and diversity

Plant KNOX homeodomain transcription factors maintain pluripotent stem cells in the shoot apical meristem, and recent studies have uncovered novel roles for the KNOX proteins in sculpting plant form and its diversity, which Angela Hay and Miltos Tsiantis review. See the Review on p 3153

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Recently a paper in Science caught my attention since its title combines the words mitotic recombination with patients and Ichthyosis. Having worked with Drosophila during my PhD and now being in a vertebrate lab, I’m well aware of the existence of tools to induce mitotic recombination to generate somatic clones of mutant cells in certain tissues. So I had a closer look at the paper to understand more about the spontaneous occurrence of mitotic recombination in humans.

“Ichthyosis with confetti” (that’s what it’s called!), or IWC for short, is a very rare sporadic skin disease. Patients display red skin because their skin barrier is defective and they often die of bacterial infections. The reason the disease carries the word confetti in its name is that in the first year of life, the otherwise reddish body starts to be covered in pale spots, resembling confetti, which increase in number and size with age.

Now it has been found that these pale spots are clones of “revertant” cells arising through mitotic recombination. Most cells in the body of IWC patients are heterozygous for a spontaneous dominant mutation in the keratin 10 (KRT10) gene that causes the red skin disease phenotype. The exact mutation in KRT10 differs between patients, but all of the mutations result in frameshifts in the same alternative reading frame of KRT10. The product of this is an arginine-rich peptide that mis-localizes to the nucleolus and thereby disrupts the keratin filament network of skin cells. The pale clones of revertant cells are formed when mitotic recombination causes loss of heterozygosity in KRT10, so that these clones no longer carry the mutation and therefore behave like normal cells. Reversion to wild type occurs at very high frequency, suggesting a general increase in the rate of mitotic recombination in these individuals. It is not yet known what causes this elevation.

So, what did I learn from this? Mitotic recombination in multicellular organisms is not just a peculiarity that can be useful for experiments in model systems, it also occurs naturally in humans. For reasons still unknown, its rate can be increased when beneficial for the cells affected. Cancer cells appear to exploit this phenomenon, increasing the rate of mitotic recombination to speed loss of heterozygosity of tumor suppressor mutations to promote their survival and growth.

Who knows, one day induction of mitotic recombination to remove undesired mutations might even be used as a therapy in humans, as long as the homozygous mutant sister cells eliminate themselves as seems to be the case in IWC. As always, the frightening part in this scenario is the possibility of losing control and causing unwanted and potentially harmful mutations. We’ll see.

Choate KA, Lu Y, Zhou J, Choi M, Elias PM, Farhi A, Nelson-Williams C, Crumrine D, Williams ML, Nopper AJ, Bree A, Milstone LM, & Lifton RP (2010). Mitotic Recombination in Patients with Ichthyosis Causes Reversion of Dominant Mutations in KRT10. Science (New York, N.Y.) PMID: 20798280

(5 votes)

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“Why are there no pop hits about Arabidopsis?” sings Karmadillo. Even though their Arabidopsis song is not a pop hit (yet?) either, Karmadillo can at least lay claim to the honour of having performed it alongside other science-themed songs on the “Reproductive Stage” at the virtual 2010 Geek Pop festival.

The song celebrates Arabidopsis as model organism, with such lines as: “That the public don’t know you, that’s unfair, but they can get your genome, thanks to TAIR.” The music video also has plenty of lab footage showing Arabidopsis in action:

Rishi Nag, the main man behind Karmadillo, lives and works in Cambridge, so I managed to catch up with him this summer and ask him about the song and how he came about writing it.

Rishi, my first question is maybe a bit obvious, but why are there no pop hits about Arabidopsis?

I think it just never hit the romantic side that roses have. The song that I wrote was meant to be about this plucky little plant that a lot of biology work is being done on.

Why did you write the song?

I work in the Department of Plant Sciences [at Cambridge University] and we had a Christmas revue at the end of the year, where people from various departments were getting together do all kinds of songs. I had the idea to write the song for that, but didn’t get it done in time. Then there was this festival called Geek Pop at the start of the year, and I had some time off over Christmas so I managed to sit down and record it. Having a deadline to submit it for Geek Pop was quite a motivating factor to finish it. [Before that] I think I just had the chorus stuck in my head for a while.

How have people responded to it?

Oh, it’s been really popular, so that’s been really nice. I wrote another song called “Brownian Motion” which is more of a physics song, which I think has been my most popular of the Geek Pop songs, I’m afraid.

How did you get interested in science?

I work in the group run by David Baulcombe, [and] I’m actually a bioinformatician/web designer. Essentially my background was nothing to do with biology, and then a couple of years ago I started doing the website for a pan-European EU-funded project called SIROCCO, dealing with [RNA] silencing in various institutions. Through that I’ve started learning more about bioinformatics, and taking on a bigger role in that. It’s been really interesting and exciting for me. I have a background as a DSP (digital signal processing) software engineer. That’s quite dead scientifically in that what you’re doing commercially is as good as it will get for the most part. Then to come into bioinformatics and learn about genetics and genes just really whetted my appetite again for science and its processes.

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by Valerie Butler

Most of us, I’m sure, can remember that AHA moment in school when we realized that science is pretty cool. Imagine how it might be for a student enrolled in a school lacking the resources to teach science well, or who was never given the opportunity to excel in anything, let alone science. What if the opportunity for an AHA moment never arrived?

This is, unfortunately, the truth for many primary and secondary school students, and it is especially so for low-income and predominantly minority communities. Students from disadvantaged backgrounds often carry stereotypes that scientists are old, white men who are out of touch with society, and many youth believe that science careers are out of their reach. The challenge then, is how to excite children about science such that they want to make a career of it?

In the United States, and now in Melbourne, Australia, science educators are doing just that with a K-12 outreach program called BioEYES. A former BioEYES student, Dasha, in a thank you note summed up the challenge facing science educators:

“I just wanted to thank you for coming to our class. I think you thought we were the worst class you ever had. All our teachers say that. Thank you for letting us use your microscope.”

BioEYES reaches out to children like Dasha who have internalized the message that they are among “the worst” and appoints them to an esteemed role, that of research scientist. By stepping into this role, students feel important and get excited about science, and for the first time they are encouraged to see this career is open to them. BioEYES plants seeds of enthusiasm for science and learning that helps inspire kids to stay in school and, for some, to pursue careers in science, engineering, math and technology fields.

One reason for the success of the BioEYES program lies in its fun, hands-on activities using live zebrafish. Over the course of the week that the BioEYES Outreach Educators are in the classroom, students learn to use the scientific method, cross the fish, observe embryo and larval development daily under a microscope, and record their findings. They learn about and are encouraged to consider scientific careers. Depending on the grade level taught, concepts in ecology, vertebrate development, stem cells and genetics may be explored. On the last day of the program, students in all grade levels observe the beating heart of a zebrafish larva. For most, this is their first glimpse of an actual heart pumping in real time, and inspires a strong visceral reaction unlikely to be duplicated by a video or picture. Many students express delight and amazement, and truly see the fish as like themselves.

Modeled on the successful BioEYES program established in Philadelphia in 2002 by Dr. Steven Farber and Dr. Jamie Shuda, BioEYES has educated more than 35,000 students nationwide. At present, one school district in the United States has their own fulltime, dedicated BioEYES Educator, and a second school district expects to develop a BioEYES Teacher Leader position for the 2010-2011 school year. In August 2010 BioEYES went international when we implemented our program in Melbourne, Australia.

Part of the appeal of BioEYES is the support it offers to teachers, many of whom (especially at the primary school level) have minimal training in science education. Prior to the BioEYES unit, teachers attend a training workshop that introduces them to the program and curriculum. For their first two years of participation, teachers co-teach the unit alongside a BioEYES Outreach Educator. In the third and subsequent years, teachers may be designated “Master Teachers” and they can teach the unit independently with materials provided by BioEYES. Master Teachers deliver the program at significantly reduced cost to BioEYES and they free Outreach Educators to work in classes that have not yet participated.

BioEYES is a nonprofit tax-exempt organization and currently operates out of the Carnegie Institution for Science in Baltimore, MD; the University of Pennsylvania in Philadelphia, PA; Notre Dame University in South Bend, IN; and Monash University in Melbourne, Australia. We have been able to deliver our programs to tens of thousands of children at no cost to their schools because of the generosity of individuals, foundations and corporations. Not surprisingly we have a close partnership with the Society for Developmental Biology not only because we are using  a developing model organism, we both share the goal of fostering a more scientifically literate society. We of course welcome your support!

Check out this video of BioEYES in action:

BioEYES in Baltimore County

For more information please visit our website, www.bioeyes.org.

(6 votes)

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In a paper published today in Cell, Detlev Arendt, Raju Tomer and colleagues reveal evidence that the cerebral cortex evolved much earlier than previously believed. Using a new technique to detect and image simultaneously expressed genes in a compact brain area, they discovered that the gene expression patterns in the olfactory processing region (mushroom bodies) of the marine worm Platynereis dumerilii are strikingly similar to that of the vertebrate cerebral cortex – too similar to have evolved independently. The last common ancestor of Platynereis dumerilii and vertebrates lived around 600 million years ago, which means that the origin of our cerebral cortex can be traced back to the Precambrian era.

Previous studies that compared brain regions between different organisms would look at shape and location of the tissues, and found no cortex-like structure in any invertebrates – not even those more closely related to us than Platynereis is. To see the similarities between the worm brain and the vertebrate cortex, Raju Tomer developed a technique called cellular profiling by image registration (PrImR). This method enabled him to see each cell’s gene activity in the worm brain, and compare this information with gene expression profiles of the vertebrate cerebral cortex.

(Image credit: EMBL/R.Tomer)

The image above shows a virtual Platynereis brain, composed of average images of the brains of 36 individual larvae at 48 hours old, with colour-coded gene activity patterns shown for each area of the brain.

The study suggests that we may need to reevaluate what is known about the evolution of the cerebral cortex. It would be interesting to use PrImR on other organisms to find out more about similar structures in other species.

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(2 votes)

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Grade 7 £28,983 – £35,646

We are seeking two Post-Doctoral Research Assistants for Professor Liz Robertson’s Wellcome Trust funded Research Group studying mammalian developmental biology at the Sir William Dunn School of Pathology.

Our programme focuses on defining the molecular cues responsible for cell allocation and tissue morphogenesis in the developing mammalian embryo.  We have exploited transgenic and ES cell technologies to investigate the key signalling pathways and transcriptional networks that regulate expansion of diverse progenitor cell populations.  Candidates with experience in construct design, high resolution imaging, cell sorting, microarrays, ChIP and/or proteomic approaches would be especially welcome.  We are seeking well trained and ambitious scientists with good organisational and communication skills.

Arnold and Robertson (2009).  Making a commitment: cell allocation and axis patterning in the early mouse embryo.  Nature Rev. Mol. Cell Biol.  10, 91-103

Morgan et al. (2009) Blimp-1/Prdm1 alternative promoter usage during mouse development and plasma cell differentiation. Mol. Cell. Biol. 29, 5813-27

Costello et al. (2009) Smad4-dependent pathways control basement membrane deposition and endodermal cell migration at early stages of mouse development.  BMC Developmental Biology 9, 54-70

Arnold et al. (2008) The transcription factor Eomes/Tbr2 regulates neurogenesis in the embryonic subventricular zone. Genes Dev. 22:  2479-84.

Maretto et al. (2008) Ventral closure, headfold fusion and definitive endoderm migration defects in mouse embryos lacking the fibronectin leucine-rich transmembrane protein FLRT3 Dev. Biol. 318: 184-193.

Arnold et al. (2008) Pivotal roles for Eomesodermin during axis formation, epithelium-mesenchyme-transition and endoderm specification in the mouse. Development 135:501-511.

Robertson et al. (2007) Blimp1 regulates development of the posterior forelimb, caudal pharyngeal arches, heart and sensory vibrissae in mice. Development 134: 4335-45.

To apply please send your CV, a cover letter and contact details of 2-3 referees to administration@path.ox.ac.uk.  Please quote reference LR/10/008

Informal enquiries welcome – please email Prof Liz Robertson at Elizabeth.robertson@path.ox.ac.uk (www.path.ox.ac.uk/dirsci).

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“You’re probably wondering why I’m here”, were the first words of Edward Marcotte’s talk at the SDB meeting last month. After all, he was about to speak about systems biology in a session on organogenesis. What followed was not only a new way to identify genes involved in developmental processes, but also a perfect example of the kind of unexpected discoveries that can be made using publicly available data.

Edward Marcotte is a bioinformatician at the University of Texas at Austin. His lab introduced the concept of phenologs to discover non-obvious disease models and candidate genes, and at the SDB meeting, as well as in a recent paper, he described exactly how “non-obvious” some of those models are: If a yeast model for angiogenesis doesn’t sound unlikely enough, the group also proposed a plant model for Waardenburg syndrome!

The concept behind phenologs is that a set of genes related to a phenotype in one organism may correspond to an orthologous set of genes in another organism. Orthologues are homologous genes between different species, but this does not necessarily mean that the same gene is linked to the same phenotype in both organisms. Marcotte looked at groups of orthologues: If a group of genes is linked to a certain phenotype in one organism, and that same group results in another phenotype in a second organism, then those two phenotypes are phenologs.

The concept of phenologs. (Figure 1B in the PNAS paper.)

In one practical example from the paper, known gene-phenotype associations from yeast were compared with known gene-phenotype associations from mice, using information from publicly available yeast and mouse genome databases. This showed that many genes that are associated with abnormal angiogenesis in mice have orthologous genes in yeast. Of course yeast doesn’t have a circulation system, so these genes can’t possibly be associated with angiogenesis in yeast, and indeed they’re not: In yeast, these same genes are involved in sensitivity to the hypercholesterolemia drug lovastatin. This suggests that lovastatin sensitivity in yeast could be a model for angiogenesis in vertebrates. To prove this, follow-up experiments showed that the transcription factor SOX13, which was identified as lovastatin-sensitive in yeast, is required for vascular development in Xenopus.

Even more surprising than finding angiogenesis genes in yeast, is that a similar comparison of phenologs suggests a plant model for Waardenburg syndrome. This disorder is caused by impaired neural crest development, and is marked by pigmentation defects and craniofacial malformations. Phenologs showed that many genes associated with Arabidopsis failing to grow in response to gravity (gravitropism) were orthologous to human genes mutated in Waardenburg syndrome, which suggests that other gravitropism genes may serve as starting points to look for other factors involved in neural crest migration.

While I was listening to this talk, I wondered whether the people who did the original yeast lovastatin screens could ever have imagined their data being used to find a new factor involved in angiogenesis. And the groups that identified gravitropism-related genes in Arabidopsis must never have thought that this could even remotely have anything to do with Waardenburg syndrome in humans! It illustrates exactly why it’s important to make data from screens and large-scale studies available to others: You often only use a small amount of the data, and buried among the rest of it is information that could be useful to people you’d never expect would benefit from it! The data in public databases speeds up research and opens up new subjects of investigation, and that is exactly why it’s there.

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(6 votes)

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Many human embryonic stem cell (hESC) researchers are now scrambling for funding and concerned about the future of their research, following a recent ruling in the United States by Chief Judge Royce C. Lamberth.  To understand this ruling, both how it came about and its implications moving forward, it’s important to take a look at the history, biologically and politically, of hESCs in the U.S.

In 1998, a group led by Prof. James Thomson, at the University of Wisconsin, isolated embryonic stem cells (ESCs) from humans for the first time.  These pluripotent cells are specifically isolated from four- or five-day-old blastocysts (pre-implantation embryos containing approximately 150 cells).

To generate the hESCs, Thomson’s group used blastocysts from in vitro fertilization (IVF) clinics with full donor consent. Since then, additional hESC lines have been created, often using blastocysts from IVF clinics that would otherwise be discarded (due to being damaged). Since IVF has become such a popular practice (now responsible for 1 in 100 births in the U.S.), there are now over half a million frozen embryos in the U.S. alone; there does not appear to be a shortage.

In 2001, President George W. Bush adopted a rather restrictive hESC policy, limiting the number of hESC lines that researchers could use and still receive federal funding; work with only 21 of the originally created lines could be federally funded (and no newly generated lines would receive federal funding). (However, work with other hESC lines could still receive private funding.)

President Barak Obama’s administration changed Bush’s policies. Specifically, in March 2009, Obama made it possible for researchers to receive federal funding for research on at least 75 different hESC lines; lines could be funded as long as the embryos used had full consent of the donors and the embryos would have otherwise been discarded (after use in an IVF clinic). However, federal funding could still not be used to generate new hESC lines.

Obama’s new policy quickly brought about a lawsuit, led by Nightlight Christian Adoptions and two adult stem cell researchers, Dr. James L. Sherley (a former MIT researcher who notoriously went on a hunger strike after being denied tenure) and Dr. Theresa Deisher (president and founder of Sound Choice Pharmaceutical Institute). The plaintiffs claimed that the new policy violated the Dickey-Wicker Amendment (established in 1996), which states that federal money cannot be used for any “research in which a human embryo or embryos are destroyed, discarded or knowingly subjected to risk of injury or death.” The Obama administration’s policy had bypassed this Amendment because it did not allow for federal funding of the generation of hESCs, but only for their downstream use.

To determine how valid the objection against hESC research is based on its use of human embryos, it’s important to understand two key aspects of hESCs’ unique biology and derivation. First, unlike adult stem cells, hESCs can be grown and expanded indefinitely, creating potentially an infinite number of hESCs from a single human embryo. Consequently, most research facilities that use hESCs do not generate the cell lines themselves, but purchase them from a banking facility (such as WiCell) or a collaborator. Second, researchers have shown that it is possible to generate a hESC line without damaging the embryo (although, admittedly, this is not how the hESC lines are typically created) (see Klimanskaya et al., 2006). Not only is it possible to create hESC lines without destroying a human embryo, or create potentially infinite hESCs from a single human embryo, but most researchers who work with these lines never encounter the donated human embryos used. However, this has not stopped Dr. Sherley and Dr. Deisher from appealing their suit.

Last year, the suit was dismissed because the plaintiffs would not be materially affected by a possible change in the policy. However, the suit went to the Court of Appeals, which reversed the ruling because it claimed that Dr. Sherley and Dr. Deisher were harmed by Obama’s policy; as they only worked with adult stem cells, theoretically they would have to deal with increased federal funding competition. In these economically tight times, one wonders how many other researchers might resort to prosecuting away their competition for funding sources. Dr. Sherley and Dr. Deisher became the only plaintiffs remaining.

On August 23rd, 2010, Chief Judge Royce C. Lamberth (who was appointed in 1987 by President Ronald Reagan) ruled to block Obama’s new hESC policy, asserting that federal funding could not be used in hESC research because the research “necessarily depends upon the destruction of a human embryo.” Judge Lamberth continued to state that, “If one step or ‘piece of research’ of an E.S.C. research project results in the destruction of an embryo, the entire project is precluded from receiving federal funding.”

Judge Lamberth claimed that his ruling was simply a return to “status quo,” but many are unclear, and understandably quite concerned, about the implications of the ruling; does this mean there will be a return to Bush administration policies, or can no hESC research be federally funded at all? The ruling has shocked the National Institutes of Health (NIH) and researchers alike, disrupting research in hESC laboratories across the country. However, the NIH already declared that the ruling would not affect grants that have already been paid this year, but renewals and grants currently being reviewed will be postponed. It will take some time to clarify the impacts of the ruling, although the Obama administration quickly announced, on August 24th, that it would appeal Judge Lamberth’s decision. However, it is not easy or efficient to simply put hESC research on hold; these cells are delicate, and require time to get going once they have been stopped.

Luckily, many hESC laboratories have alternative, private funding that is not affected by this ruling. The most significant remaining funder of hESC research is probably the California Institute for Regenerative Medicine (CIRM), which in 2004 was given $3 billion (through Proposition 71) to spend on stem cell research by Californian voters. (Luckily, my laboratory in the University of California, Santa Barbara, is one of such stem cell facilities funded primarily by CIRM.)

For more coverage on Judge Lamberth’s ruling against Obama’s hESC policies, see The New York Times’ article on “U.S. Judge Rules Against Obama’s Stem Cell Policy,” The Los Angeles Times’ article on “Ruling a blow to stem cell research,” National Public Radio’s article on “Obama Appeals Stem Cell Ruling; Some Work to Stop,” or The Forum on Science, Ethics, and Policy’s article on “Court Ruling Prevents Funding of Embryonic Stem Cell Research.”

I would be interested to hear about hESC policies in other countries, especially in the European Union. From what I’ve heard, there seems to be great variation, even within the EU.

(4 votes)

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At the recent SDB meeting in Albuquerque, Eric Olson took the stage twice: on Friday morning he spoke in the organogenesis session about the role of microRNAs in muscle, and on Sunday evening he entertained the attendees of the conference’s closing ceremony with his band, the Transactivators. In between these two performances, I asked him a few questions about science, music, and doing research funded by a country singer.

What are you working on at the moment?

We’re working on the role of microRNAs in responses to a number of muscle diseases. We’re looking at how microRNAs regulate the sensitivity of the heart after stress, and how they regulate atrophy of muscle or diseases of the vascular system. We’re trying to develop new therapeutics that can manipulate microRNAs in the settings of those disorders.

You also play in a band, can you tell me a bit about that?

I have a band I started about five years ago, called the Transactivators. It’s made up of all scientists, and we just play Rock ‘n Roll. We’re a cover band, so we play all the seventies and eighties rock music that everybody likes to listen to. We have a good following in Dallas. We play in a bar there and people seem to like to see us outside of our normal, scientific, daily functions.

How did you meet the other band members? Through work?

Yes, I knew that some people I worked with knew how to play music, but we’d never played together. So we started getting together. One thing led to another and it just took off.

Are there any other music projects that you’ve been working on?

No, this is the only one. I play at home by myself, but in terms of organized projects, this is the only one. It’s kind of tough because I’m really busy and I travel all the time. So just to coordinate everyone’s schedules is a challenge.

You also hold the Annie and Willie Nelson Professorship in Stem Cell Research at the University of Texas Southwestern Medical Center. How did that come about?

The president of our institution knew that I was interested in music. When Willie Nelson’s kids were coming to UT Southwestern to get a checkup, he arranged for me to meet Willie Nelson’s wife and kids, and we talked about what I was working on. Annie Nelson – his wife – got really excited, so she got Willie to throw a benefit concert and raise money for our stem cell effort.

[As a result] the lead guitar player of my band and me have been on Willie’s tour bus, and been backstage at several of his concerts.

What does Willie Nelson think of research? Does he know anything about it, or is he mainly interested in the therapeutic side of it?

He’s interested in worthwhile causes, and that includes stem cell research.

—

The Node sadly had to miss the closing banquet of the SDB meeting, so I didn’t get to see Eric perform, but Steve Farber of the Carnegie Institution of Washington was there, and said: “Eric gave a great seminar that got me thinking about microRNAs and their regulation. Then he and his band got a sizable proportion of the banquet attendees dancing on the lawn by the aquarium.  I was surprised when I heard some Jimi Hendrix in the mix. Way too much fun!”

For an impression of what the band looks and sounds like, watch this YouTube video.

(4 votes)

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Non-muscle myosin II translates cilia polarity

In the brain, cilia on the multiciliated ependymal cells that line the brain ventricles circulate cerebrospinal fluid over the brain surface. To generate this directional fluid flow, the ependymal cell cilia and their basal bodies must be orientated in one direction. This ‘rotational’ polarity is regulated by the planar cell polarity (PCP) pathway. Recent reports have revealed that the basal bodies are also localised at the anterior of the ependymal cells but how is this ‘translational’ polarity established? Using a new method for time-lapse imaging of ventricular walls, Kazunobu Sawamoto and co-workers now show that, in mice, the anterior migration of basal bodies in the apical cell membrane during ependymal cell differentiation establishes translational polarity (see p. 3037). Inhibition of the PCP protein dishevelled 2, which disrupts rotational polarity, does not affect translational polarity, the researchers report. Instead, their pharmacological and genetic studies identify non-muscle myosin II as a key regulator of translational polarity. Thus, different mechanisms regulate the orientation and distribution of basal bodies in ependymal cells.

SNP links Dlx gene regulation to autism

Several neurodevelopmental disorders, including autism, have been linked to the aberrant development of γ-aminobutyric acid (GABA)-expressing interneurons in the mammalian forebrain. Dlx homeobox genes control the development of these interneurons and now, on p. 3089, Marc Ekker and colleagues report that a rare, autism-associated single-nucleotide polymorphism (SNP) in an ultraconserved regulatory element (I56i) in the DLX5/DLX6 bigene cluster affects Dlx5/Dlx6 regulation in the mouse forebrain. The researchers show that the SNP, which lies in a functional protein binding site, reduces I56i enhancer activity in the developing mouse forebrain and in adult GABAergic interneurons. Notably, Dlx proteins have a reduced affinity for the variant I56i protein binding site in vitro, they report, which reduces the transcriptional activation of the enhancer by Dlx. The researchers propose, therefore, that impaired I56i enhancer activity by the SNP could affect the auto- or cross-regulation of the DLX5/DLX6 bigene cluster, thereby disrupting cortical interneuron development and contributing to the developmental abnormalities that underlie autism.

Symmetric neural progenitor divisions Notch up

During development, the balance between neural stem cell self-renewal and differentiation is carefully controlled to ensure that the correct number of neurons is produced to build functional neural networks. In the Drosophila optic lobe, as in the mammalian cerebral cortex, neuroepithelial (NE) cells initially divide symmetrically to expand the stem cell pool, before switching to asymmetric division to generate neurons. Andrea Brand and colleagues now report that Notch regulates this important cell fate transition (see p. 2981). By comparing the transcriptomes of microdissected NE cells and neuroblasts, the researchers show that Notch signalling pathway members are preferentially expressed in NE cells. Notch mutant cells are extruded from the neuroepithelium and undergo premature neurogenesis, they report. Furthermore, a wave of proneural gene expression transiently represses Notch activity in NE cells to enable the transition from symmetrically dividing NE cell to asymmetrically dividing neuroblast. This progression resembles that seen in the vertebrate cerebral cortex, leading the researchers to propose that neurogenesis regulation could be conserved between these two systems.

Changing identities: neuronal transdifferentiation

Traditionally, cellular differentiation is thought to be an irreversible commitment to a given cell identity. So, for example, differentiated neurons cannot generate new cells or adopt new identities. Now, however, Melissa Wright and colleagues provide evidence for the transdifferentiation of dorsal root ganglia (DRG) sensory neurons in zebrafish larvae (see p. 3047). Using time-lapse microscopy, the researchers track DRG neurons in wild-type zebrafish and in zebrafish mutant for the nav1.6 voltage-gated sodium channel. Some DRG neurons migrate ventrally from their normal position and then adopt a phenotype characteristic of sympathetic neurons in both types of larvae, they report, but more DRG neurons transdifferentiate in the mutant larvae. Furthermore, although the loss of sodium channel expression promotes the migration of DRG neurons, once in a new environment, these neurons transdifferentiate regardless of sodium channel expression. Thus, the researchers conclude, differentiated sensory neurons retain the plasticity needed to transdifferentiate when challenged by a new environment, a finding that suggests new strategies for the treatment of nervous system diseases.

Heartfelt responses to opposing FGF/BMP signals

Congenital heart disease – the commonest type of human birth defect – is the result of abnormal early heart development. In this issue, two papers investigate how opposing fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signals control the differentiation of the secondary heart field (SHF) and anterior heart field (AHF) cardiac progenitors during early vertebrate heart development.
On p. 3001, by isolating and culturing chick SHF mesoderm, which forms the myocardium and smooth muscle of the heart’s arterial pole (the outflow region of the heart), Mary Hutson and colleagues show that this tissue contains stem cells that can differentiate into myocardium, smooth muscle and endothelial cells. By treating SHF (arterial pole) progenitor cultures with combinations of growth factors and inhibitors, the researchers show that BMP promotes myocardial differentiation but not proliferation of the arterial pole progenitors, whereas FGF promotes their proliferation and smooth muscle cell differentiation but inhibits myocardial differentiation. These and other results indicate that myocardial differentiation of the SHF progenitors requires BMP signalling and downregulation of the FGF/ERK pathway and suggest that the FGF pathway maintains the SHF stem cell pool early but promotes smooth muscle cell differentiation later.

On p. 2989,, Eldad Tzahor and colleagues provide further insights into how opposing BMP and FGF signals regulate cardiogenesis by studying the differentiation of chick AHF progenitors, which contribute to the right ventricle and to the arterial pole. By perturbing signalling pathways in vitro and in vivo, the researchers show that, as in SHF progenitors, BMP promotes myocardial differentiation of AHF progenitors by blocking FGF/ERK signalling and that FGF signalling prevents their premature myocardial differentiation. They also show that BMP4 induces the expression of several neural crest-related genes and that cranial neural crest cells are required for BMP-dependent myocardial differentiation of the AHF progenitors. Thus, Tzahor and colleagues suggest, BMP and FGF signalling pathways coordinate the balance between the proliferation and differentiation of cardiac progenitors in the AHF through regulatory loops that act in multiple tissues.

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