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.

(1 votes)

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Postdoctoral Positions are available for highly qualified and motivated candidates to study the physical principles of morphogenesis in the Davidson Laboratory at the University of Pittsburgh in the Department of Bioengineering. The laboratory focuses on studying the molecular-, cellular, and tissue-scale processes that regulate mechanical properties and force-production during morphogenesis. Projects involve a combination of biophysics, cell biology, bioengineering, and embryology.

Candidates will have recently completed a PhD and have strong background in either biophysics, cell and developmental biology, or cell- and tissue- mechanics. Candidates with expertise with biochemistry, quantitative microscopy, microrheology, microfabrication or computer simulation are preferred. The research environment at the University of Pittsburgh includes a dynamic community of bioengineers, developmental biologists, cell- and tissue-level biomechanics, and theoretical biologists. Nearby resources include the John A. Swanson Micro and Nanotechnology Laboratory and the Pittsburgh Supercomputing Center. Contemporary Pittsburgh is a diverse vibrant city undergoing a renaissance led by world class Universities and the University of Pittsburgh Medical Center. The University of Pittsburgh is an Equal Opportunity Employer. Women and minorities are especially encouraged to apply.

Interested applicants should forward their statement of research interests, CV, and a list references to:

Lance Davidson
Department of Bioengineering
Biomedical Science Tower 3, Room 5059
3501 Fifth Avenue
University of Pittsburgh
Pittsburgh PA 15260
(email) lad43@pitt.edu
(web) http://www.engr.pitt.edu/ldavidson/

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Worth 1000 words?

http://blogs.nature.com/news/thegreatbeyond/2010/08/a_zebrafishs_first_minutes_of.html

[update 31/8: I added the first of the videos (below) – Eva]

(The original paper is in Science)

(2 votes)

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It seems that following on the tracks of Cell Press, which is reducing the maximum number of supplemental figures to one per manuscript figure, now J. Neuroscience is doing away with it altogether. Hooray?

I agree that it is not a very good thing at times that the amount of Suppl Figs has risen (or sunk) from useful to occasionally ridiculous (20+ figures!). Yes, it is useful to be able to add a few control experiments, or the validation of a mouse knockout, and a good place to put especially large datasets, but now it’s become an excuse to either bury data that isn’t super solid (in hopes that reviewers won’t pay too much attention), or from the other side, an open invitation for reviewers to ask for more (It’s like a reverse Oliver Twist: “Can I have more please?”; “MORE!?”).

And for the most part, it’s a rather annoying exercise to have to go download the suppl materials. Why can’t journals not put the supplementary pdf together with the main paper pdf? I do it all the time, it’s a simple feature in Acrobat, so is that so much to ask for from a publisher? Cell Press does it, Nature Cell Biology does it, but that’s about it.

So, Supplementary/Supplemental figures/data? Good, bad, ugly? Discuss. Perhaps we can help influence some journals that are paying attention.

(3 votes)

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Some Canadian postdocs are awaiting the next academic year with bated breath: will they earn less than they did during their PhD, or twice as much as their colleagues?

Canada’s 2010 research budget, announced this past spring, was full of surprises for the thousands of postdoctoral researchers in the country. To promote top-level talent, the government put aside $45 million for the next five years to award a select group of postdocs with $70,000 per year. These Banting post-doctoral fellowships are almost twice as much as the average Canadian postdoc salary of approximately $35,000-$40,000. Applications for the prestigious awards have opened on August 10, and are being accepted until November 3, 2010. But the lucky few who get the top awards will also receive another, slightly less pleasant, surprise: postdoctoral fellowships in Canada are no longer tax exempt. Even postdocs who previously paid no taxes on the funding they received, will be charged next year. Until now, postdoctoral stipends often fell under the same – tax-free – umbrella as student scholarships. Surprisingly, this now means that a fully-funded PhD student can end up with more money than they will receive as a postdoc paying taxes on a basic postdoc fellowship!

With such mixed funding news, reactions from young Canadian researchers have been all across the board. What do you think: is the $45 million well spent on the new competitive awards (boosting the international prestige of these researchers, and perhaps being a way out of the previously discussed issue of “too many postdocs”), or would you rather have seen a continuation of the tax exemption for postdoc stipends? The Banting fellowships are open to international applicants, too: would knowing that there was a very small chance of a competitive postdoc salary lure foreign researchers to Canada, or would it succeed in keeping Canadian graduates from seeking top funding elsewhere in the world?

(image by lsiegert on Flickr)

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Many of you are probably familiar with the web comic Piled Higher and Deeper (PhD), which chronicles the lives of graduate students and perceptively points out some of the peculiarities of academia. Recently, we met up with the comic’s creator, Jorge Cham, and talked about graduate school, recognizable academic situations that cross all disciplines, and procrastination.

(Thanks to Node readers Kat, Pablo, and Sandra for providing some of the questions.)

When did you start drawing Piled Higher and Deeper?

I started during my first term in grad school, so I was definitely not supposed to be drawing comics. I was a teaching assistant, I was a research assistant, I was taking classes – but I saw this ad in [The Stanford Daily] newspaper calling for comics, and I just thought I would submit something nobody had ever really written about or made fun of: people trying to get their PhDs.

How did you manage to find time to combine that with grad school itself?

I didn’t sleep a lot during that semester! But I started publishing a new comic five days a week, and that quickly became only three times a week.

Many of your readers, including myself, grew up with your comic throughout grad school. Meanwhile, some of us have graduated, but a lot of your characters still haven’t. Are they ever going to graduate?

Yeah, the series will not go on indefinitely. I definitely have endings or events for all of the characters, whether they graduate or not.

Will there be a spin-off postdoc comic then?

Heh! Well, they might become postdocs. One of the characters is now a postdoc, but it will probably still be called “Piled Higher and Deeper”

We noticed that the comic works well for a lot of different fields. The readers of the Node are all developmental biologists, and you don’t have a biologist character in the PhD comics, but a lot of the things are still recognizable. Do you notice that a lot of the situations you write for, for example, the engineer characters are applicable to any field?

I do it on purpose. When I first started grad school I happened to know a lot of people who were in many different fields: Anthropologists, economists, engineers, geophysicists – and they were all friends! Just listening to them I could tell that they were all sharing the same experience. So for me, from the very beginning that was something that was interesting to me, so that’s the way I wrote the comics. I grounded the characters in a specific department, so that there’s a bit of realism there, and you get the sense that they are doing something. But I try to write the dialogue so that it generally speaks to academics and grad students in all disciplines.

That being said, there are specific things that biologists have to deal with that don’t occur in other fields, like the fact that you have to take care of living things on the weekend. Has anyone ever requested a biologist character?

Yeah, a lot. In fact, I’m very familiar with the idea of being beholden to experiments like that, because I worked in a neuroscience lab for two years. Somebody once described it as “your life being run by the menstrual period of rats”. I have a character who is going to focus on biology, but probably not for another year or year-and-a-half.

You also travel around to give talks about procrastination. A lot of visitors to the Node drop by during a break from work, and I’m sure they’d like to know if there’s any value to procrastination.

I don’t like to talk about whether procrastination is good or bad. I just like to talk about the fact that you do it, and that you probably do it for a reason. There’s a lot of flexibility in grad school, and it always feels like it never ends. There’s always something more that you could be doing – something more that you should be doing –so a lot of times people find themselves procrastinating. What I like to say is that procrastination is not necessarily bad, but that it’s sometimes an important part of the creative process, and can reveal what you really want to do, and what your real passions are. If you find that you’re not spending as much time as you should be on, for example, writing this particular chapter for this particular professor, it maybe means that you don’t really want to write it. Instead of feeling bad about it, you should just realize it, and focus on something else.

Finally, one of our readers in South America asked when you’re coming to the Southern Hemisphere

You just have to invite me – that’s pretty much how it works!

Part of a collection of panels Jorge drew at Sci Foo, where we met for the interview.

Part of the interview in audio format:
[audio:https://thenode.biologists.com/wp-content/uploads/2010/08/jorge-cham.mp3|titles=jorge cham]

(6 votes)

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(This interview by Kathryn Senior originally appeared in Development on August 10)

Shin-Ichi Nishikawa is Group Director of the RIKEN Center for Developmental Biology in Kobe, Japan, where his stem cell research focuses on understanding the mechanisms involved in cell differentiation. He joined Development as an editor in 2009. We interviewed Shin-Ichi to find out about his interest in developmental biology, about the event that made him change career from being a practicing physician to a researcher, and his current research interests.

Looking back, when do you first remember being interested in science?

This was quite early in my life, when I was still a pupil at elementary school. I remember very clearly the day that the Sputnik satellite was launched by the Soviet Union – on October 4, 1957. I heard the news and was amazed that something the size of a beach ball had been sent into orbit around the Earth. We didn’t know it then, but this was the dawn of the space age, the beginning of the space race and the start of my life-long passion for science.

What path did you follow in your early career?

I was desperate to work in a scientific field but I was not good at maths or physics, so becoming a researcher in physics or space technology wasn’t really an option. I decided to study medicine and got my MD at the Kyoto University School of Medicine in 1973. I then worked as a chest physician for about 7 years, completing an internship and residency at the Kyoto University Chest Research Institute. My plans at that stage were to carry on in medicine, and I would very likely have stayed on track if I had not caught hepatitis when treating one of my patients.
(more…)

(5 votes)

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The Bicoid gradient, epigenetic control of BMP signalling, haematopoietic stem cells and more…here are the highlights from the current issue of Development:

The Bicoid gradient gets into shape without nuclei

Morphogen gradients provide key positional information during embryogenesis but how they are established is not well understood. A gradient of the transcription factor Bicoid is known to provide Drosophila embryos with positional information along their anterior-posterior axes. Since Bicoid is enriched in nuclei, nuclei have recently been proposed to act as potential traps or sites of degradation that could slow down Bicoid diffusion from the anterior pole and hence contribute to the observed Bicoid gradient. On p. 2857, Oliver Grimm and Eric Wieschaus address this issue experimentally and find that the Bicoid gradient is shaped independently of nuclei. Using mutated Bicoid with impaired nuclear localisation, they show that the resulting gradient of this protein is indistinguishable from that formed by normal Bicoid protein. They also show that the initial centre-to-surface redistribution of Bicoid and the scaling of the gradient are not influenced by Bicoid nuclear accumulation. Based on these findings, the authors propose that nuclei do not play a role in shaping the Bicoid gradient.

Spinal cord development BuMPs into epigenetics

During spinal cord development, transcription factors and signalling proteins, such as the BMPs, are involved in neural tube (NT) patterning and in inducing neural differentiation. Although epigenetic modifications are known to regulate the expression of key neural development genes in stem cells, whether they have a role in spinal cord development remains unclear. On p. 2915, Marian Martínez-Balbás and colleagues study histone H3 lysine 27 trimethylation (H3K27me3) in vivo during chick embryo neurogenesis. They show that global levels of H3K27me3 increase along neurogenesis and regulate BMP signalling within the NT. Using microarray analysis, they find that the expression of Noggin, a BMP inhibitor, is repressed by H3K27me3. Importantly, they show that, in response to BMP activity, the histone demethylase JMJD3 interacts with the Smad1/4 complex to demethylate and thereby activate the Noggin promoter. This reveals a novel pathway by which BMP signalling can regulate its own activity within the spinal cord by modulating expression of its inhibitor Noggin.

microRNA regulation of Hox genes: RNA tails matter

The Hox family of transcriptional regulators plays a central role in specifying segment identity along the anteroposterior axis of animal bodies. The Drosophila Hox gene Ultrabithorax (Ubx) is dynamically expressed during development and controls the development of posterior thoracic and anterior abdominal segments. On p. 2951, Claudio Alonso and colleagues show that during development the Ubx gene produces multiple transcripts that vary in their visibility to microRNAs (miRNAs). They demonstrate that different parts of the embryo express Ubx transcripts that contain variable 3′ UTRs, each harbouring a distinct set of miRNA target sites. The differential distribution of these transcripts during development is independent of miRNA-mediated degradation but is instead due to an in-built system that processes mRNAs according to developmental context. They also show that other Hox genes, such as Antennapedia, abdominal-A and Abdominal-B, exhibit similar developmental RNA processing and propose that developmental processing of 3′ UTR sequences is a general molecular strategy that allows spatiotemporal control of mRNA-miRNA interactions during development.

Haematopoietic differentiation: lessons from development

Efficient production of haematopoietic stem (HPS) cells from embryonic stem (ES) cells or from induced pluripotent stem (iPS) cells requires a thorough understanding of haematopoietic differentiation pathways. On p. 2829, Gordon Keller and colleagues show that generation of HPS cells from ES and iPS cells follows the same steps as haematopoietic development in the embryo. They induced ES cells with known agonists of embryonic haematopoiesis (activin A, BMP4 and VEGF) and identified two temporally distinct populations of cells expressing the haematopoietic marker Flk1. The gene expression profiles, cell surface markers and lymphoid potential of the early Flk1-positive population resemble those of the first site of embryonic haematopoiesis, whereas the cells that expressed Flk1 at a later stage correspond to a later stage of haematopoiesis. The ability to identify and isolate different stages in the progression from ES or iPS cells to HPS cells will facilitate the study of the generation of blood cell lineages and might improve the efficiency of production of transplantable cells.

Branching out: strigolactones modulate auxin transport

Shoot branching in plants occurs after bud activation in axillary meristems, which are stem cell clusters along the shoot. This process is repressed by strigolactones by a poorly understood mechanism. One model suggests that strigolactones do not act on the bud directly, but inhibit shoot branching by preventing auxin transport out of the bud. Ottoline Leyser and co-workers now show, on p. 2905, direct evidence in support of this model. The researchers treated Arabidopsis stem segments with a synthetic strigolactone, GR24, and found that this reduced auxin transport. Furthermore, they ruled out a direct effect of strigolactones on bud growth by showing that treatment of a solitary bud with GR24 alone had no effect on bud outgrowth, but that GR24 increased the inhibitory effect of an additional auxin source. In addition, they demonstrated that GR24 enhanced competition between two buds on the same stem. Collectively, these data support the model that strigolactone inhibits shoot branching by regulating the efflux of auxin from axillary buds.

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