Pak1-ing a punch in lumen formation

The generation and maintenance of correct lumen size and shape is essential for the function of tubular organs. Now, Monn Monn Myat and co-workers report that p21-activated kinase (Pak1) plays a novel role during lumen formation in Drosophila embryonic salivary glands (see p. 4177). The researchers show that Pak1 regulates the size and elongation of the apical domain of individual epithelial cells in the developing gland by decreasing and increasing E-cadherin levels at adherens junctions and basolateral membranes, respectively. Pak1 mediates these effects, they report, through Rab5- and Dynamin-dependent endocytosis of E-cadherin. Moreover, constitutively active Pak1 induces the formation of multiple intercellular lumens in the gland, an effect that is dependent on Rab5 and Dynamin, and on the Pak1 substrate Merlin. Together, these results identify a crucial role for Pak1 and E-cadherin endocytosis in lumen size and shape determination in fly salivary glands, and highlight a mechanism for multiple lumen formation, a process that occurs in pathological conditions such as breast ductal carcinoma in situ.

Shh signalling out-Foxed by cilia

Sonic hedgehog (Shh) signalling controls cellular differentiation in the neural tube by regulating a poorly defined gene regulatory network. To better understand this network, James Briscoe and colleagues have undertaken a genome-wide expression screen in chick neural tube and, on p. 4271, they identify the forkhead transcription factor Foxj1 as an Shh target gene in this tissue. Foxj1, they report, is expressed in the chick and mouse neural tube in cells that constitute the floor plate (FP), a neural tube organising centre. Foxj1 expression is associated with the formation of long motile cilia in several cell types and, consistent with this, the authors show that chick and mouse FP cells produce primary cilia longer than those produced elsewhere in the neural tube. Finally, they show that Foxj1 expression in the neural tube attenuates Shh signal transduction by altering cilia structure and modifying the intracellular localisation of the Gli proteins that mediate Shh signalling. Together, these data reveal a novel cilia-dependent mechanism that modulates cellular responses to Shh signalling.

Leaves send mobile signals for size

Organ size in plants and animals is tightly controlled, and partly determined, by cell size and number. Plant leaves, for example, exhibit compensation, in which defective cell proliferation triggers increased postmitotic cell expansion. Now, Hirokazu Tsukaya and colleagues (p. 4221) identify two novel pathways coordinating cell proliferation and expansion in Arabidopsis leaves. Two Arabidopsis mutants, the loss-of-function ANGUSTIFOLIA3 (AN3, a transcriptional co-activator) mutant and the overexpressor KIP-RELATED PROTEIN2 (KRP2, a cyclin-dependent kinase inhibitor) mutant show compensation: in an3 mutant leaves, cell numbers decrease by ~70%, whereas cell size increases by 50%. Using the Cre/lox system, the authors generated leaves chimeric for AN3 and KRP2 expression, and investigated whether compensation occurs in a cell-autonomous or non-cell-autonomous manner. An3-dependent compensation, they report, is indeed non-cell-autonomous and occurs via an intercellular signal restricted to one half of leaves. Conversely, compensation caused by KRP2 overexpression occurs cell-autonomously, possibly via a mitotic cell cycling defect. Future work should shed more light on these events and identify the transmitted signal.

Ongoing Phox2 locks in neuronal differentiation

During neuronal differentiation, expression of the transcription factors that determine neuronal identity often continues after their downstream genetic program has been launched. Is this continued expression required for neuronal differentiation? On p. 4211, Jean-François Brunet and colleagues address this question by inactivating the paired-like homeobox genes Phox2a and Phox2b, which specify several classes of visceral neurons, after the developmental timepoint at which they act to initiate visceral neuron differentiation. They report that ongoing Phox2b expression is required in branchiomotor and visceromotor neuronal precursors after their initial specification to maintain their molecular signature, migration pattern and cellular differentiation. Similarly, maintenance of noradrenergic neuron differentiation during embryogenesis requires the ongoing expression of Phox2b in sympathetic ganglia and of Phox2a in the main noradrenergic centre of the developing brain. Thus, neuronal differentiation does not always unfold as a transcriptional ‘cascade’ in which downstream events are irreversibly triggered by an upstream regulator. Instead, as seen here, it sometimes requires continuous input from so-called ‘terminal selector genes’.

Hippo links growth control to tissue homeostasis

Both tissue repair and tissue homeostasis require stem cells that proliferate to replenish lost cells, but the way in which adult stem cells respond to damage and switch between homeostatic and rapid proliferative states is not well understood. In the Drosophila midgut, intestinal stem cells (ISCs) maintain homeostasis, and, in response to damage, can proliferate rapidly following activation of the Jak/Stat pathway. In this issue, two papers demonstrate that Drosophila ISC proliferation, and hence intestinal regeneration, are regulated by the Hippo (Hpo) tumour suppressor pathway, providing an exciting new link between growth control and stem cell proliferation.

On p. 4147, Nicolas Tapon and colleagues examine the effects of Hpo pathway inactivation in the midgut by overexpressing Yorkie (Yki), a progrowth target that is usually repressed by the Hpo pathway. They report that Yki overexpression in differentiated cells increases ISC proliferation non-cell-autonomously without affecting differentiation, and induces the expression of the Jak/Stat pathway ligand Unpaired. The authors also observe that Yki target genes are induced by bacterial infection, and suggest that the Hpo pathway acts to sense cellular stress within the midgut. Finally, using RNAi, they show that Yki is also required within ISCs to drive proliferation in response to bacterial-induced tissue stress. Based on their findings, they propose that the Hpo pathway is a mediator of the Drosophila midgut regenerative response.

In a second, related paper, Norbert Perrimon and co-workers (p. 4135) demonstrate that Yki overexpression in ISCs induces proliferation cell-autonomously, whereas Yki loss has no effect on ISCs during normal homeostasis. They also show that Yki activity is required in ISCs to mediate the proliferative response to tissue damage, and propose that this effect is elicited by downstream targets that are involved in proliferation and survival. Importantly, they report that, prior to tissue damage, Yki is also repressed by the atypical cadherins Fat and Dachsous, which are upstream components of the Hpo pathway. From their findings, the researchers propose that Yki is inactive under normal homeostasis but becomes activated to induce ISC proliferation when cell-contact cues, and thus Hpo signal transduction, are disrupted by tissue injury.

Also…

Germline segregation in metazoans can occur during or after embryogenesis and often involves a common set of genes. Juliano, Swartz and Wessel now propose that this gene set represents a conserved germline multipotency programme operating in germ cells and multipotent progenitors.

See the Hypothesis article on p. 4113

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Being at the end of the planet Earth and organizing an international meeting is not easy. Even harder is to prepare and hold a course intended for an international audience. But the organizing committee of the Fifth International Meeting of the Latin American Society for Developmental Biology, together with the Society for Developmental Biology, managed to make both events possible, with an outstanding response from students and researchers.

First, it was developed the short course entitled “Concepts and Model Organisms in Regenerative Biology”, in Santiago, Chile. The course was composed by theoretical and practical sessions, focused on the regenerative abilities of model organisms, and expert  researchers were invited as speakers and to show to the students about the techniques used in the model organisms of their expertise area. Some invited scientist were Brigitte Galliot, Richard Behringer, Panagiotis Tsonis, Katia del Rio-Tsonis, Alejandro Sánchez-Alvarado, José García-Arrarás and others. The enormous effort and patience of these researchers, together with the incredible amount of work of the local organizing committee (specially Juan Larraín, Miguel Concha and Miguel Allende) made possible the success of this experience.

The course was followed by the meeting in Santa Cruz, a small town in a part of Chile located in the center of the country, known by its vineyards, wine and the nice climate. The reception opening consisted in a walk by the local museum, which has interesting collections, including one of the biggest amber collection with animal and vegetal fossils preserved inside them, and fossils from the ancient fauna in Chile. After the visit to the Museum, a cocktail with chilean wine was waiting for all the students and researchers. The following was simply a success: five days of excellent talks and poster sessions. We enjoyed the presence and talks of Janet Rossant, Allan Spradling, Claudio Stern, Edward de Robertis, Carl Phillip Heisenberg, Roberto Mayor, John Wallingford, Joachim Wittbrodt, Kenneth Poss, Jonathan Slack, the speakers invited to the course and many more. The poster sessions were very exciting; the wine made easy to share and talk with the authors. Personally, the meeting was a complete success, considering that almost eight months ago, the fifth most powerful earthquake in recorded history happened in Chile (actually, Santa Cruz is located in one of the regions of Chile most affected by the earthquake, remembered also by Cristian Undurraga here at The Node, in this post), and also considering the long distance travelled by many of the attendees and the almost two weeks that some of the invited speakers (participating in the short course) stayed in Chile.

I uploaded some pictures of the meeting. It is necessary to mention that all of this success was possible with the outstanding work of many people, including Ida Chow from the SDB.  Please enjoy the pictures, and those of you that attended the meeting and/or the course, please fell free to comment and share your experience.

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Science is held pretty highly in Japan. The country has produced 15 Nobel Prize winners in the science disciplines, including two in the field of chemistry this year. But perhaps a little less in the international press’ limelight is Dr. Yoshiki Sasai, winner of the Osaka Science Prize. This honor is like the Japanese version of a science-biased Oscar for local scientists and is awarded each year to a person who has made a major contribution to physical science, engineering, agriculture, biology, medicine, pharmacology or information science by helping to advance scientific understanding and developing new technology. And this year the prestigious honor has been awarded to a developmental biologist.

Sasai is a Group Director in the RIKEN Center for Developmental Biology, a visiting professor at the National Institute of Physiological Sciences and an affiliated professor at Kyoto University Graduate School of Medicine. Adding to this impressive resume, Sasai was also a visiting professor at Lund University Faculty of Medicine and a research fellow at UCLA School of Medicine.

He was awarded with the Osaka Science Prize for his work in the analysis of organizational principles in brain development. His particular interest of research lies in understanding how the complexity of the fully-formed brain arises from a nondescript clump of cells in the embryo by studying very early neurogenesis and the mechanisms of neuronal differentiation.

It is heartening to know that developmental biologists are being recognized worldwide. It can, of course, only be a good thing.

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The 3rd Latin America Course on ES cells and Development will be in Cuernavaca, Mexico. It provides extensive hands-on experience and an incredible line-up of speakers. The course can take up to 8 UK PhD students, post-docs, or young investigators, and it is fully funded. Please visit:

http://www.escellslatinamerica.org/

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The Society for Developmental Biology participated in the first USA Science and Engineering Festival held October 10-24, 2010 in Washington, DC.  SDB sponsored four separate events throughout the festival in an effort to share the field of developmental biology with the community.  This included a teacher workshop based on the BioEYES K-12 science education program, Nifty Fifty speaker Marnie Halpern who spoke at a Maryland high school, a public lecture featuring Nobel laureates Eric Wieschaus and Martin Chalfie with Alexandra Joyner and Mary Dickinson at the Carnegie Institution, and a 2-day Expo on the National Mall in Washington, DC.

Visitors to the SDB expo booth were able to observe live developing frog and zebrafish embryos, color masks of their favorite model organisms, and participate in the Evolution Thought Trail exercise on the homology of the vertebrate forelimb.  There was an overwhelming excitement from students, parents, teachers, and scientists to participate in future science festivals.

(2 votes)

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The Gairdner Awards is Canada’s foremost international award, recognizing medical researchers for their work which has contributed significantly to improving quality of life.  There are five awardees each year and 76 of the 298 Gairdner awardees to date have gone on to win the Nobel Prize.

Lectures celebrating scientific excellence in medical research take place across Canada during the third week of October and culminate in Toronto with the Gairdner Awards lectures.  This year in Toronto, the Gairdner lectures kicked off on October 27 with an afternoon of lectures focusing on the eradication of malaria.  On the final day of the lectures, October 29, the Gairdner Symposium was held, highlighting research in epigenetics and genome function.

On October 28, sandwiched between the two outstanding sets of seminars was the main event – the annual Minds that Matter symposium with lectures by the 2010 Gairdner Awards recipients. The 2010 Gairdner International Laureates are:
Dr. William Catterall for the discovery of the voltage-gated sodium channel and calcium channel proteins and the elucidation of their function and regulation
Dr. Pierre Chambon for the elucidation of fundamental mechanisms of transcription in animal cells and the discovery of the nuclear receptor superfamily
Dr. William Kaelin, Dr. Peter Ratcliffe, and Dr. Greg Semenza each for his work in the identification of molecular mechanisms of oxygen sensing in the cell

Also giving lectures were the Wightman and Global Health Laureates.  Dr. Calvin Stiller is the 2010 Canada Gairdner Wightman Laureate, being recognized as a pioneer in organ transplant and diabetes research as well as an innovator in the Canadian biotech industry.  Dr. Nicholas White is the 2010 Canada Global Health Laureate for his research in the effectiveness of artemesinins in the treatment of malaria and elucidating the basis for the use of ACT to prevent resistance.

This year’s lectures covered topics from molecular biology to epidemiology, highlighting the importance of medical research in all fields of biology and health care.  The Gairdners will, no doubt, continue to bring to the forefront significant advances in medical research.

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Glamour, fame, red carpets, flashing lights. It’s not what you usually get as a top scientist, but why not? Why should overnight reality TV stars get more attention than people who spent years researching how the world works? This lack of attention to the important role of scientists was a driving force behind the second annual “Rock Stars of Science” campaign. Men’s glossy magazine GQ is giving 17 researchers the glamour treatment: designer fashion, meeting rock stars, and a multi-page spread in their December 2010 issue.

Posing on the first page of the feature (shown above) are TGF-β scientist Joan Massagué, cancer researcher Craig B. Thompson, and 2009 Lasker winner Charles Sawyers. Dressed to the nines, and giving the camera an ice-cold glare, they’re accompanied by Debbie Harry of Blondie fame. A few pages further is another memorable sight: Nobel Laureates Phil Sharp (sporting a leather jacket) and Liz Blackburn (almost unrecognizable without glasses), together with Anne and Nancy Wilson of Heart:

Other musicians who were happy to pose with scientists in the GQ photo spread are Timbaland, Keri Hilson, Bret Michaels, B.o.B, and Jay Sean, who himself once studied medicine in London: “I was halfway through my degree; it’s when my first record deal presented itself… But I’ll always be a fan of science.”

With surveys showing that many people in the US are unable to name a single living scientists, GQ and the philanthropic Geoffrey Beene foundation hope that the Rock Stars of Science campaign will improve the image of science by profiling its stars. There is no attempt to explain any of the research – just like a photo spread of an actor or musician wouldn’t try to analyze their work. It’s just scientists being shown as, and with, rock stars, to make them look cool and hopefully get people interested in the researchers and the work they do.

The campaign is also supported by a website with profiles of the scientists. Elsewhere online, science writer Chris Mooney, who was involved with the campaign, looks back at the first installment of the photo spread last year. He reveals what happened to the scientists who participated in 2009, and why posing with rock stars may just be the only way for researchers to get through to the public.

The full list of scientists featured in the 2010 Rock Stars of Science campaign:
Stephen B. Baylin, Elizabeth H. Blackburn, Susan J. Blumenthal, Geraldine Dawson, Frank L. Douglas, Bernard A. Harris, Catriona Jamieson, Emil Kakkis, Frank M. Longo, Joan Massagué, Mehmet Oz, Eric M. Reiman, Phillip A. Sharp, Charles L. Sawyers, Craig B. Thompson, Mehmet Toner, Michael W. Weiner

Jealous? Keep up the research, and maybe one day it will be you rubbing shoulders with musicians in a glossy photo shoot.

(Image credit: Kurt Iswarienko)

(6 votes)

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Cold Spring Harbor has just published a new book on cell death by Doug Green, a larger-than-life character who will be familiar to anyone who’s ever been to an apoptosis conference. In this video, Doug talks about the apoptosis machinery and explains why cell death is critical during development.

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I’m Nish, a 3^rd year PhD student in Kate Storey’s lab at the University of Dundee. Over the past year, I’ve been involved in running PiCLS, the PhD association here at the College of Life Sciences in Dundee. Unfortunate acronyms aside, it has the most interesting year of my PhD so far. I thought I’d write a bit about my experiences with PiCLS, hopefully to encourage other students to be part of something similar and maybe even getting other academics thinking about supporting students taking part as well.

To give you a bit of background about PiCLS, it was started in late 2008 by a group of students who had been organising various student events like retreats and decided to form an official organisation for students with support from the college. The aim of this organisation was to help students from different fields network. Dundee may be a small place, but with students working in the lab late hours and sometimes in unsociable labs, it can be difficult to meet other students and socialise with them.

Also, more importantly, it gave students a voice in important decisions made by the College. As PhD students aren’t contracted employees but are often treated as such, it is important that we are heard.

I joined the PiCLS board in its 2^nd year. The previous board had established PiCLS in the College of Life Sciences quite well, organising workshops, seminars, a ceilidh (a Scottish dance – some of you may remember the one at this year’s BSDB/BSCB meeting in Warwick) and retreats and we wanted to take this further. As well as academic seminars, we organised career seminars, more social events like pub nights and sports competitions between departments. We even put together a symposium where we invited students from across the country and some big names from different fields to give talks like Matthias Mann, Susan Gasser and Seth Grant.

I learnt a lot in my year on the PiCLS board. I found out a lot about how institutes like the College of Life Sciences are run; especially the logic behind some of the decisions made that at first don’t seem right. I also appreciate how hard it is to organise a symposium/conference. We were very lucky in that we had the expertise of many people who had organised conferences in Dundee at our disposal.

Above all, I had a great lot of fun being part of this society. I got to do some really interesting things that most PhDs haven’t done and I got to know a lot of new people in the process, not just students and academics. It also helped build contacts that may be useful later in my career. These contacts are also useful if you want to consider forging a career outside of science, something that a lot of us students should consider, especially in these testing time. If anyone gets the chance to start up or join a PhD society, I would strongly recommend they take it.

I may have some bias in this statement, being part of PiCLS, but when I think about the things we achieved and the feedback we’ve been given, I hope that every institute thinks about supporting a PhD student society.

In the spirit of social networking, here is a link to our Facebook page with photos and details of events – http://tinyurl.com/38uj5ko.

(4 votes)

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The current issue of Development is now online! Here are the research highlights:

Klf5: a multifaceted regulator of cell fate

Kruppel-like transcription factors (Klfs) induce and maintain pluripotency in embryonic stem cells (ESCs), and Klf4 is one of the factors used to create reprogrammed iPS cells. The role of Klfs in the specification of the three lineages of the pre-implantation embryo – trophectoderm (TE), epiblast (EPI) and primitive endoderm (PE) – however, is not known. On p. 3953, James Wells and colleagues report that Klf5 is a dynamic regulator of all three lineages. Using Klf5 mutant mice, they show that Klf5 deficiency results in developmental arrest at the blastocyst stage, and causes defective TE formation, reduced EPI marker expression and increased PE marker expression in blastocysts. Conversely, overexpression of Klf5 suppresses the PE lineage in blastocysts and upregulates pluripotency-related genes in ESCs. Finally, Klf5-deficient blastocysts in culture fail to form pluripotent colonies and instead have an increased contribution of PE cells compared with control embryos. The authors conclude that Klf5 is a multifaceted regulator of cell fate specification during pre-implantation development.

LGL-1 on PAR with polarity

In the early C. elegans embryo, polarity is established via myosin-dependent contractions that lead to the asymmetric distribution of partitioning-defective (PAR) proteins; PAR-3 and PAR-6, together with the atypical protein kinase C (PKC-3), localize to the anterior cortex, whereas PAR-2 becomes enriched at the posterior cortex. In Drosophila and mammals, PAR-2 is not expressed, but numerous proteins, including Lethal giant larvae (Lgl), act together with the other PAR proteins to establish polarity. Kenneth Kemphues and colleagues (p. 3995) show that the C. elegans homolog of Lgl, LGL-1, functions redundantly with PAR-2 to maintain polarity in the C. elegans embryo. Like PAR-2, LGL-1 localizes to the posterior cortex of the embryo in a PKC-3-dependent manner, and its overexpression is sufficient to rescue loss of PAR-2 function. Importantly, they show that LGL-1 prevents myosin from accumulating in the posterior cortex of the embryo. This provides new insights into the way in which LGL-1 might influence myosin-dependent contractile flows and PAR protein localization, and hence cell polarity.

Nervous asymmetry

Left-right asymmetry is a conserved, but poorly understood, feature of animal nervous systems. Now, Robert Horvitz and colleagues reveal how a neuronal bilateral asymmetry is established in C. elegans (p. 4017). In C. elegans, the left-right asymmetric ABaraap cell lineage generates the single unpaired MI neuron and the e3D epithelial cell on the right and left sides, respectively, of the animal. The researchers show that the proneural bHLH genes ngn-1 and hlh-2, and the Otx homeodomain gene ceh-36 specify the MI neuron and establish this asymmetry – the determination of which occurs in the precursor cells for the left and right branches of the ABaraap lineage. Importantly, this initially cryptic asymmetry triggers activation on the right side only of a transcriptional cascade that then acts through multiple rounds of cell division, with CEH-36 functioning in the MIgrandmother cell, but not in the e3D-grandmother cell, to induce expression of NGH-1/HLH-2 in the MI-mother cell. Given their results, the researchers suggest that an evolutionarily conserved Otx/bHLH pathway establishes nervous system bilateral asymmetry in C. elegans and in other animals.

Shh: homeodomain interpreters at work

Morphogen gradients play an important role in establishing cell diversity during development. But how are small differences in the concentration of extracellular signals translated into a precise, robust transcriptional output in responding cells? On p. 4051, Johan Ericson and colleagues reveal that a homeodomain transcription factor feedback circuit is involved in the interpretation of the Sonic hedgehog (Shh) gradient that patterns the vertebrate ventral neural tube. They report that Nkx2 homeodomain proteins, which are induced by Shh, amplify Shh responses and are required for the induction of floor plate (FP) cells and p3 progenitors, the ventral-most neural tube cells. By contrast, the Pax6 homeodomain protein suppresses ventral fates by antagonising Shh signalling. Finally, the researchers report that a temporal switch in neural potential, rather than exposure of cells to different Shh concentrations, determines the spatial patterning of FP cells and p3 progenitors. They conclude, therefore, that dynamic, non-graded changes in responding cells are essential for the interpretation of graded Shh signalling.

Vascular instruction of liver development

Alagille syndrome (AGS), which is caused by mutations in the Notch ligand jagged 1 (JAG1), is characterized by defective intrahepatic bile duct (IHBD) formation, but the mechanistic origins of this defect have been unclear. Now, on p. 4061, Luisa Iruela-Arispe and colleagues report that the conditional inactivation of Jag1 specifically in the developing portal vein mesenchyme (PVM), and not in the PV endothelium, of mice gives rise to AGS-like liver defects. They demonstrate that loss of Jag1 from the PVM leads to defective IHBD morphogenesis. Cytokeratin-positive bilary epithelial cells (BECs) surround the portal vein of these mice, indicating that their initial specification is Jag1 independent, but these cells fail to develop into mature bile ducts. Using in vitro spheroid co-cultures of isolated BECs and PVM, the authors show that loss of Jag1 from the PVM inhibits BEC aggregation, demonstrating that the PVM is a vital source of Jag1 signalling during BEC morphogenesis. The authors, thus, propose that the developing vasculature provides instructive signals for liver morphogenesis.

War of the whorls

Animal bristles, hairs and other surface appendages are orientated with the body axes and with adjacent structures to form precise macroscopic patterns. Unusually, in frizzled 6-null (Frz6–/–) mice, the hair follicles are orientated randomly in utero but reorientate after birth to create large-scale hair patterns. Jeremy Nathans and coworkers now describe the spatial and temporal dynamics of this hair follicle reorientation process (p. 4091). By analysing follicle orientations in Fz6–/– mice during late gestation and early postnatal life, they discover that an apparently local alignment pattern generates macroscopic patterns that compete with each other. Reorientation of the hair follicles at the junctions between different territories leads to the formation of whorls and crosses, which disappear within a week as the territories expand to generate long-range order. The researchers suggest that mouse hair follicle reorientation, which closely resembles the wing and thoracic hair realignments seen in Drosophila planar cell polarity mutants, could be driven by a follicle repulsion or interfollicle chemoattractant mechanism.

Also…

SRY is the transcription factor product of the sex-determining gene on the mammalian Y chromosome. In this issue, Kashimada and Koopman provide an updated account of how SRY triggers the cascade of molecular events that drive testis formation while inhibiting ovarian development.

See the Primer article on p. 3921

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