Dear Reader,

My name is Dávid Molnár, I’m a third year Ph.D. student in the Department of Human Morphology and Developmental Biology at Semmelweis University (Budapest, Hungary). I’d like to share the story of my summer internship with You!

Thanks to the generous offer of Guojun Sheng, the team leader of the Laboratory for Early Embryogenesis in RIKEN Center for Developmental Biology (Kobe, Japan), I could spend three months in his lab in a Japanese world leading institute. It changed my working progress, my view on science and the way how I got there taught me a lot.

in the front: Guojun Sheng in the background: Cantas Alev and Ruben Buys

Almost a year ago in September of 2009, I lived the ordinary life of Hungarian Ph.D. students. The preparation for the ISDB 2009 conference brought a little excitement into my days and started a series of unpredicted events. Those days were also unique for me, because that was the first time in my life when I travelled by plane.

In the charming city of Edinburgh I met many people, who had just been well known names on the headers of articles before, but there I saw the persons themselves behind the papers. In the labyrinth of the exhibitors’ stands I found the desk of RIKEN Center for Developmental Biology. I had known before that it was a melting-pot of scientists from all over the world studying developmental biology on advanced level but at that time , due to my lack of foreign research experience, I couldn’t imagine how this kind of institute worked. I took a RIKEN brochure. At the end of the conference I realized that my baggage was heavy, so I started sorting out all the papers and tearing out the useful pages. That was the moment when I saw a report of Brendan McIntyre’s work who was a post doc in Dr. Sheng’s lab. The key words “blood, hematopoiesis, CD34, chicken embryo” aroused my interest immediately.

After the conference several weeks elapsed until I read those torn pages again. That time we just started introducing in situ hybridization to our techniques. We were interested in different hematopoietic markers e.g. CD34, but there was no commercial antibody against the chicken equivalent of this protein, and we were not that experienced in molecular biology methods. I sent an e-mail to Brendan McIntyre who was really helpful. He had already left Japan but answered my questions and forwarded my e-mail to team leader Guojun Sheng. From that time we exchanged plenty of letters with Dr. Sheng in which he shared all his remarks and advice about the ideas and experiments we were planning.

Surprisingly in late February I got an e-mail form Dr. Sheng: he offered me a short time internship in his laboratory in the RIKEN Center for Developmental Biology.

Then a hurrying organization started with visa application, obtaining the certificate of eligibility, exchanging letters, photos numerous documents. Because my financial sources were limited I had to look for external funding. Coincidentally one of my collegues after a lunch break mentioned an application which supports young researchers. We checked it out together – it was the Development Travelling Fellowship. First I estimated a low chance to receive the scholarship, but I convinced myself to try it. Getting closer and closer to the 1st of June, the determined date of departure, I got more and more excited. Nearly one week before my trip I got the result: I would get support from Development. It was unbelievable how lucky I was!

In less than a year I ended up with an invitation to Japan and a successful grant application, and soon after my first flight I got the chance to travel by plane again – immediately to the other half of the world. Since then I’ve been frequently thinking about what had happened if I hadn’t taken a brochure, if I hadn’t taken those torn pages, if I hadn’t been brave enough to write an e-mail to Dr. Sheng. The main conclusion of the previous year: always go with eyes wide open, because you never know what sort of chances will be served by life!

The turtle eggs have just arrived!

My experiences in Japan absolutely fit into this series of successful events. In Guojun Sheng’s lab I spent three hard-working months under the supervison of Cantas Alev. During this time I tasted a little molecular biology in the fascinating environment of RIKEN CDB. I learned how to generate in situ probes and carry out whole mount in situs. I worked on N^o1 machines in the company of great scientists. Of course I traveled around the Kansai area and I managed to visit Okinawa too, but the main advantage of my stay – beside its scientific impact- is that I got to know how life goes on in Japan. At RIKEN CDB I experienced the atmosphere of high level science outside the institute I saw a peaceful and safe country with delicious food, inspiring history, beautiful geography and I was surrounded by kind and friendly people. I really enjoyed it and it’s easy to get used to it!

Unfortunately my internship finished just when I felt the people around me were pretty close to myself and work raised the possibilities of different projects. Nowadays I usually think about my friends who I met in Japan.

This year taught me to look for the chances and to be brave enough to use them, to realize the necessity of foreign experiences and how to fit to a changed environment.

I’m really thankful to Guojun Sheng and Cantas Alev. Their support brought me one step closer to molecular biology and extended my view on other fields of developmental biology. I truly believe that this three-month internship opened new doors which may result in a long-time collaboration between the two laboratories.

At last but not least I must say thank you to each and every member in the Laboratory for Early Embryogenesis (in alphabetical order): Cantas Alev, Manjula Brahmajosyula, MengChi Lin, Hiroki Nagai, Yukiko Nakaya, Fumie Nakazawa, Kanako Ota, Guojun Sheng, Erike Sukowati, Wei Weng, Yu Ping Wu. I’m also thankful to Ms. Naoko Yamaguchi who helped arrange the visit.

Finally I’d like to express my gratitude to all those at The Company of Biologists and Development who spent time on reading my application and supported my plan to come true!

Laboratory for Early Embryogenesis – RIKEN CDB – Kobe, Japan

Developmental Biology and Immunology Lab – Department of Human Morphology and Developmental Biology, Semmelweis University – Budapest, Hungary

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

Oct1: essential for trophoblast development

Most POU family transcription factors are temporally and spatially restricted during development and play pivotal roles in specific cell fate determination events. Oct1 (Pou2f1), however, is ubiquitously expressed in embryonic and adult mouse tissues; so, does Oct1 have a developmental role? On p. 3551, Fatima Cavaleri and colleagues report that Oct1 regulates trophoblast development during mouse embryogenesis. The researchers generate Oct1-null embryos and show that they fail to develop beyond the early primitive streak stage. Analysis of the mutant embryos reveals that they lack normal maternal-embryonic interfaces because of reduced extra-embryonic ectoderm (ExE) formation and the absence of the ectoplacental cone – two extra-embryonic tissues generated from the trophectoderm cells that overlie the inner cell mass (which forms the embryo). Other experiments indicate that Oct1 loss is incompatible with the derivation of trophoblast stem cells, which normally reside in the ExE. The researchers suggest, therefore, that Oct1 is primarily required for the maintenance and differentiation of the trophoblast stem cell compartment during early post-implantation development.

Schwann cells: more than just insulators

How neurons connect to their targets during embryogenesis has been intensively studied, but what maintains the position and connections of nerves during postembryonic growth? To investigate this, William Talbot and colleagues study the development of the posterior lateral line nerve (PLLn) in zebrafish embryos and larvae (see p. 3643). Using transmission electron microscopy, the researchers show that the PLLn – a peripheral nerve that innervates sensory organs in the epidermis – initially grows in the epidermis but that shortly after axon outgrowth, the epidermal basement membrane degrades and reforms on the nerve’s opposite side, thereby repositioning the nerve into the subepidermal space. Analysis of mutant and chimeric embryos shows that Schwann cells, which myelinate peripheral nervous system axons, are required for this process; without them, the PLLn becomes severely disorganised. Thus, by remodelling tissues in the vicinity of nerves, Schwann cells, which are traditionally regarded as static insulators, could play an important role in the proper organisation of nerves that innnervate other sensory organs during postembryonic growth.

WUSCHEL robustly plants stem cell homeostasis

Plant stem cell populations are maintained by the precise coordination of stem cell division and the rates of cell division and differentiation among stem cell progenitors. In the growing tips of higher plants (shoot apical meristems, SAMs), stem cell daughters produced by infrequent stem cell division in the central zone (CZ) are displaced towards the surrounding peripheral zone (PZ), where they divide faster and their progeny differentiate into leaves or flowers. Now, Venugopala Reddy and co-workers report that the homeodomain transcription factor WUSCHEL (WUS) mediates stem cell homeostasis in Arabidopsis (see p. 3581). The researchers use transient manipulation of WUS expression and live imaging to show that elevated WUS levels in the CZ induce CZ expansion and increase PZ cell division rates. Conversely, decreased WUS levels lead to a smaller CZ, reduced PZ cell division rates and increased responsiveness of PZ cells to the plant hormone auxin, which leads to enlarged organ primordia. Thus, by regulating stem cell numbers and growth and differentiation patterns, a single transcription factor robustly mediates plant stem cell homeostasis.

Haematopoietic cluster locations made transparent

Haematopoietic clusters – cell aggregates that are associated with endothelium in the large blood vessels of midgestation vertebrate embryos – play a pivotal but poorly understood role in the formation of the adult blood system. To date, the opaqueness of whole embryos has prevented the systematic quantitation or mapping of all the haematopoietic clusters in mouse embryos but, on p. 3651, Tomomasa Yokomizo and Elaine Dzierzak remedy this situation. Using a technique to make whole mouse embryos transparent, combined with immunostaining and three-dimensional confocal microscopy, they show that the number of clusters peaks at embryonic day 10.5. Clusters are heterogeneous, they report, and localise to specific vascular subregions, such as the middle subregion of the aorta near to its junction with the vitelline artery. Finally, by combining flow cytometry and functional studies, the authors demonstrate that haematopoietic progenitor and stem cells are enriched within the cluster population. Together, these results provide novel insights into the spatial development of the adult blood system in mice.

Chordin downregulation waves on aortae fusion

During development, extensive remodelling of the embryonic vasculature, the first organ to develop, ensures that the embryo’s cells are constantly supplied with oxygen and nutrients. The first major vascular remodelling event in mammalian and avian embryos is fusion of the bilateral dorsal aortae at the midline to form the dorsal aorta. Takashi Mikawa and co-workers now show that a developmental switch in notochord activity signals this fusion in chick and quail embryos (see p. 3697). Prior to fusion, the researchers report, the notochord secretes positive and negative factors that together block the initiation of aortae fusion. Notably, whereas the expression of positive vascular regulators is maintained during fusion, the expression of negative regulators such as chordin, an antagonist of the positive regulator BMP, is downregulated along the anteroposterior axis. The discovery of this novel mechanism for modifying vascular pattern – modulation of vascular inhibitors without changes in positive vascular regulator levels – could aid the development of treatments for vascular injury.

Cut to fly airway remodelling

In insects that completely metamorphose, such as Drosophila, embryonically specified imaginal cells remain dormant until the larval stages when their coordinated proliferation and differentiation generates various adult organs. Now, on p. 3615, Chrysoula Pitsouli and Norbert Perrimon describe how embryonic cells – spiracular branch (SB) tracheoblasts – remodel the Drosophila abdominal airways during metamorphosis. The adult fly tracheal system consists of branched tracheal tubes (which transport air into the insect’s body) and spiracles (the external respiratory organs, which are surrounded by epidermal cells). The researchers show that embryonic SB tracheoblasts are multipotent cells that express the homeobox transcription factor Cut, which is necessary for their survival and normal development. SB tracheoblasts, they report, give rise to three distinct cell populations at the end of larval development, which generate the two components of the adult tracheal system and the surrounding epidermis. This dissection of the molecular events that underlie the formation of an adult tubular structure in Drosophila might shed light on mammalian tubular organ development, suggest the researchers.

Also…

In the first of our new Evolutionary crossroads in developmental biology series, Prigge and Bezanilla introduce Physcomitrella patens, a moss from this ancient, non-vascular plant lineage, studies of which are distinguishing ancestral developmental mechanisms from those that are novel innovations in flowering plants. See the Primer on page 3535.

This article is the first in a series of Primers on organisms and phyla that have been particularly informative for studying the evolution of developmental mechanisms and morphology. Other articles in this series will be published over the next 12 months.

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The FASEB Excellence in Science Award is awarded annually to a woman whose research has made an exceptional contribution to the field of biological sciences. In 2011, this award will go to developmental biologist Gail Martin, of the University of California, San Francisco.

Martin’s current work focuses mainly on the role of FGF signalling in organ development, but in 1981 she was the first  to isolate embryonic stem cells from mouse blastocysts grown in vitro, and in fact coined the term “embryonic stem cell”.

The Society for Developmental Biology (SDB) has written a profile of Gail Martin that is currently in press at Developmental Biology. Martin was president of the SDB in 2006-2007, and in her interview she addresses her passion for mentoring students and postdocs, and her interest in sharing unpublished results. She will receive her award at the 2011 SDB meeting, to be held in Chicago in July.

(3 votes)

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In the US, basic plant research is relatively underfunded compared to other fields, with most of the available money going directly towards the development of practical agricultural applications.

Last year, the Howard Hughes Medical Institute (HHMI) organized a meeting called “Future Horizons in Plant Science”, where select scientists in the field concluded that there was a need for a funding boost in plant science. Now, the HHMI, together with the Gordon and Betty Moore Foundation (GBMF) is providing this boost in the form of $75 million for 15 researchers over the next five years.

This is a one-time competition to specifically target plant researchers at a time when they are not receiving as much funding as their colleagues working on animal organisms. To qualify, scientists need to currently be working as tenured or tenure-track researcher at a US institution. Applications for the new grants are due on November 9.

See HHMI press release for full details, including a link to the application website with even more information.

(Arabidopsis painting by Emmanuel Boutet through CC-BY-SA license on Wikimedia commons.)

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Hello to all of you Node readers!  My name is Erin Campbell and I’m the blogger behind HighMag Blog, a blog that features cell biology images a few times a week.  The great Eva Amsen contacted me about featuring some images on The Node, so I’m excited to be part of this growing community forum.  The first image I’m blogging about is from a paper in the October 1 issue of Development, and features the biologically complex and visually stunning Drosophila ovary.

Ovarian cyst development begins in the germarium, with a stem division that produces the cystoblast, which then divides 4 more times.  One cell in this 16-cell mass eventually becomes the oocyte, and the remaining cells serve as nurse cells to support the growth of the oocyte.  This 16-cell cyst then becomes a separate egg chamber after being surrounded by follicle cells and budding off of the germarium.  The hierarchy of signals and events that allow the differentiation of the cyst has been well studied, and a recent paper fills in the gaps in our understanding of this process.

Tastan and colleagues report that the Drosophila homolog of the human ataxin 2-binding protein 1 (A2BP1) gene functions in the intermediate stages of cyst differentiation, bridging the expression of early and terminal differentiation markers.  Mutations in A2BP1 cause defects in cyst differentiation, as shown in the images above.  Germline cells are labeled in green using anti-VASA antibodies, membranes are labeled in red using an anti-1B1 antibody, and DNA is labeled in blue.  Compared with control ovaries, mutants exhibit a range of phenotypes:  A2BP1^CC00511 cysts have extra nurse cells, A2BP1^f02600 cysts exhibit a mildly tumorous phenotype, and A2BP1^f01889 cysts have an extreme tumorous phenotype.

Reference: Ömür Y. Tastan, Jean Z. Maines, Yun Li, Dennis M. Mckearin and Michael Buszczak (2010). Drosophila Ataxin 2-binding protein 1 marks an intermediate step in the molecular differentiation of female germline cysts. Development 137, 3167-3176. Paper can be found here.

(10 votes)

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Robert Edwards has just been announced as winner of the 2010 Nobel Prize in Physiology or Medicine, for his work on in vitro fertilization (IVF)

We speculated about the winners a few weeks ago, and he was not among anyone’s guesses, but this is a very exciting and timely choice. Just last Friday I mentioned that the Human Fertilisation and Embryology Authority will likely be cut. This is the body that regulates all IVF research in the UK, where Edwards work took place. Hopefully this award will bring the relevance of such regulatory bodies in the spotlight again.

Edwards worked together with gynecologist Patrick Steptoe, who died in 1988. Nobel Prizes are not awarded posthumously, which explains why he’s not included in the award.

The Nobel Prize website will be livestreaming all announcements of Nobel Prize winners this week. The Chemistry prize – which has predominantly been awarded to biology-related research the past decade – is announced on Wednesday.

(6 votes)

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In an attempt to tighten the country’s budget, the UK government wants to cut a large number of arms-length non-governmental organisations. These “quangos” (quasi-autonomous non-governmental organizations) include regulatory bodies, advisory organs, and other committees.

Until last week, there were only vague speculations as to which funds would be cut, but the news has become more certain now that the BBC has received a leaked document specifically listing 177 non-governmental organizations that are to be cut. Among those is the Human Fertilisation and Embryology Authority (HFEA), which regulates legal and ethical aspects of anything involving IVF, but also sets standards and licensing requirements for any research done on human embryonic stem cells or human embryonic developmental studies in the UK.

Without the HFEA, who would oversee this area of research? This is a question the BBC asked HFEA chairwoman Lisa Jardine, who explained that the current functions of the HFEA would probably be split in three portions, with the research using human embryonic tissue ending up in a new regulatory body. Since that new body is not yet set up, she assumes that the HFEA will remain in charge of regulations until an appropriate alternative has been set up. (If you’re in the UK you can watch her response in a video, otherwise you can read a summary and partial transcript in this article on BioNews which gives a lot of background information).

On the HFEA website is a list of research projects that they have approved in the past. As you can see, it contains many fundamental developmental biology and stem cell research projects. Delays in approving such research in the UK would affect progress within the field, so hopefully Jardine’s prediction will hold true and cutting HFEA funding will not result in a gap in licensing.

The impending demise of the HFEA is not the only worry British stem cell and human embryo researchers have at the moment. The news comes at a time when UK-based researchers in all areas of science are threatened with cuts in research funding that would allow funding only for top and/or commercially viable projects. With scientists taking to the streets to protect funding for basic research, and with important regulatory bodies such as the HFEA under threat, interesting times are ahead for researchers in the UK.

Meanwhile, on the other side of the Atlantic, things could not be more different for hESC researchers: Not only is the US increasing basic science funding rather than reducing it, but it has just been announced that the federally imposed ban on stem cell research (previously on the Node) has been lifted, bringing US stem cell projects back on track. Quite the opposite story. Are any other countries currently awaiting regulations that affect stem cell or developmental biology research?

(3 votes)

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(This interview originally appeared in Development on September 28, 2010)

The International Society for Stem Cell Research (ISSCR) held their annual conference in San Francisco this June. At the time, the President of the society was Irving Weissman, who is currently on the board of directors of the ISSCR as past President. He is Professor of Pathology and Developmental Biology and also the Director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine, where he works on the generation of myeloid and lymphoid lineages from haematopoietic stem cells. At the ISSCR meeting, we asked Professor Weissman about his role on the board of directors of the ISSCR, and also about the meeting and the field of stem cell research in general.

Thank you for taking the time for a quick interview. Are you enjoying the conference so far?

Of course, for those few moments I have without administrative duties.

What have been your highlights of the conference these first two days?

Well, there are different kinds of highlights. There is of course the highlight that just before the conference we launched our (the ISSCR’s) website on people in clinics who are practising for-profit, unproven therapies (www.closerlookatstemcells.org). This is our way of providing patients and their care-givers with the kind of advice they need in order to avoid being promised treatments that have neither the hope of treating or curing the disease nor of providing good medical practice.

How long have you been involved with the ISSCR; was it from the very start?

Yes, I was a member of the founding group, but I didn’t want the job of ISSCR President until it was more established.

How have you seen the ISSCR change over the past eight years?

I think we went from under a thousand people to nearly four thousand, both as members and as people who are participating in these meetings. We have also formed an alliance with the journal Cell Stem Cell.
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A fateful look at early mouse lineage specification

The first cell lineages specified in the mouse embryo are the trophectoderm (TE), which generates the embryonic portion of the placenta, and the inner cell mass (ICM). The ICM subsequently forms the pluripotent epiblast (EPI, which produces the embryo) and the primitive endoderm (PrE, which generates other extraembryonic structures). Two papers shed new light on these crucially important early embryonic specification events.

On p. 3383, Janet Rossant and colleagues investigate the role that the intercellular adhesion molecule E-cadherin plays in the divergence of the TE and ICM. By embryonic day 3.5, the TE has formed a polarised epithelial layer that encloses the apolar ICM. The researchers show that the normal epithelial morphology of the TE is disrupted in mouse embryos lacking both maternal and zygotic E-cadherin function but that individual cells in the blastocyst still initiate TE- and ICM-like fates. Interestingly, most of the cells express the TE marker Cdx2, which suggests that organised epithelium formation is not necessary for TE-specific gene expression. Furthermore, individual cells in these embryos still generate an apical membrane domainthat correlates with Cdx2 expression. Thus, the epithelial integrity mediated by E-cadherin is not required for Cdx2 expression but is essential for setting normal TE/ICM ratios in mouse embryos.

On p. 3361, Anna-Katerina Hadjantonakis and colleagues identify a role for platelet-derived growth factor (PDGF) signalling in PrE expansion in mouse embryos. The PDGF receptor-α (PDGFRα) is an early marker of the PrE lineage and of extra-embryonic endoderm (XEN) cells, which can be isolated from mouse blastocysts as derivatives of the PrE lineage. By combining live imaging and lineage analysis, the researchers show that Pdgfra expression coincides with that of GATA6, the earliest expressed transcription factor in the PrE lineage. GATA6 expression, they report, is required for Pdgfra transcriptional activation, and PDGF signalling is essential for the establishment and proliferation of XEN cells in culture. Moreover, implantation-delayed Pdgfra-null mutant blastocysts contain reduced PrE cell numbers and, surprisingly, increased EPI cell numbers, indicating that reciprocal signalling between PrE and EPI tissues might regulate compartment size within peri-implantation mammalian embryos.

For more on early mouse lineage segregation, see also the review by Fredrik Lanner and Janet Rossant on p. 3351.

OMA-1/2: repressors of translation and transcription

Primordial germ cell specification requires global transcriptional repression. In C. elegans, the zygote (P0) undergoes four successive asymmetric divisions to generate the germline precursors P1, P2, P3 and finally P4, the germline founder. OMA-1 and OMA-2 (OMA1/2), cytoplasmic proteins degraded after the first mitotic cycle, repress global transcription in P0 and P1 by sequestering TAF-4, an RNA polymerase II pre-initiation complex component, while the maternal protein PIE-1 represses transcript elongation in P2-P4. Now, Rueyling Lin and colleagues report that OMA proteins repress transcription in P2-P4 indirectly by maintaining PIE-1 expression (see p. 3373). OMA-1/2, they show, repress zif-1 mRNA translation in oocytes; zif-1 encodes the substrate-binding subunit of the E3 ligase that marks PIE-1 for degradation. MBK-2, a kinase that is activated after fertilisation, controls OMA1/2 function, report the researchers. Thus, they suggest, MBK-2 phosphorylation of OMA1/2 acts as a key developmental switch in the oocyte-to-embryo transition by converting OMA proteins from specific translational repressors in oocytes to global transcriptional repressors in embryos.

Shh: new TWISTs to limb patterning

Sonic hedgehog (SHH) controls anterior-posterior (A-P) patterning in the mammalian limb. Its expression is normally restricted to the posterior limb bud but when expressed ectopically, it can change digit number and/or identity. Several transcriptional factors regulate Shh expression in the limb bud but how do they function together? On p. 3417, Xin Sun and co-workers report that interactions between two negative regulators of Shh expression (the ETS transcription factors ETV4/5 and the bHLH transcription factor TWIST1) and a positive regulator of Shh expression (the bHLH transcription factor HAND2) control A-P limb patterning in mice. By examining mutant limb buds, the researchers show that Twist1 is required to inhibit Shh expression in the anterior limb bud, and that it acts with the Etv genes to antagonise Hand2. Moreover, biochemical data indicate that the ETV proteins inhibit Shh expression by regulating the dimerisation of TWIST1/HAND2. Together, these findings highlight the importance of a precise balance between positive and negative regulators of Shh expression during limb A-P patterning.

Muscling in on motoneuron specification

Mammalian skeletal muscles contain several types of muscle fibres, each characterised by its contraction speed and molecular properties. Individual motor axons innervate a few dozen muscle fibres, usually all of the same type. How this striking ‘motor unit homogeneity’ is established is incompletely understood but, on p. 3489, Joshua Sanes and colleagues reveal that, in mice, signals from the muscle fibres influence the molecular properties of motoneurons that innervate them. The lack of markers for motoneuron types has impeded the study of motor unit homogeneity. Here, however, the researchers show that the motoneurons that innervate slow muscle fibres selectively express the synaptic vesicle protein SV2A and carry it to their nerve terminals. Notably, overexpression of the transcriptional co-regulator PGC1α in muscle fibres, which converts them to a slow phenotype, increases the number of SV2Apositive motoneurons. The researchers propose, therefore, that retrograde signals from muscles integrate with previously described anterograde influences of the nerve on the muscle fibre to match the properties of these synaptic partners to each other.

LIN-42-ing up development and stress

Environmental stresses, such as nutrient fluctuations, can affect developmental progression in animals. C. elegans larvae, for example, normally develop into adults through four larval stages under the control of heterochronic (developmental timing) genes such as lin-42, a homologue of the circadian rhythm gene period. But, when times are hard, C. elegans forms long-lived dauer larvae, an alternative third larval stage. Now, Ann Rougvie and co-workers report that lin-42 functions in dauer entry (see p. 3501). Loss of lin-42, they report, makes animals hypersensitive to dauer formation under stressful conditions, whereas misexpression of lin-42 in pre-dauer stages inhibits dauer formation. Other experiments suggest that LIN-42 acts in opposition to the ligand-free form of the nuclear receptor DAF-12, which integrates external cues and developmental decisions. Together, these results suggest that LIN-42 and DAF-12 are intimate partners in the decision to become a dauer larva and raise the possibility that Period-like proteins play a conserved role in coordinating intrinsic timing mechanisms with environmental conditions.

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A recent paper in PNAS describes the development of MiniPromoters: human DNA promoters of less than 4 kb, designed to drive gene expression in specific areas of the brain. The initiative is called the Pleiades Promoter Project, and so far they have confirmed brain-region specific activity in knockin mice for 27 of their MiniPromoters. The final goal is to produce 160 fully characterized MiniPromoters to drive gene expression in defined brain regions.

The project is a spin-off of the Mouse Atlas Project (hence the name “Pleiades”: in Greek mythology, the Pleiades were the daughters of Atlas). To create the MiniPromoters, the researchers have computationally identified regulatory regions associated with brain-region or cell-type enriched gene expressions. Information about region-specific expression came from the Mouse Atlas Project as well as from the Allen Brain Atlas, which maps the human brain.

Several MiniPromoters driving LacZ in different areas of the mouse brain. (Part of Figure 5 from PNAS paper)

The MiniPromoters are designed to work in both mouse and human brains. While the Pleiades website emphasizes the ultimate goal of selective target delivery in gene therapy, the MiniPromoters can also be used to drive reporter expression in cell types of interest, for example to follow development of particular areas of the brain.
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