Here are the highlights from the current issue of Development:

Integrating integrin signals for neocortical growth

Within the developing neocortex, multiple progenitor cell types contribute to neuronal production, and the properties and relative abundance of these populations help to define the extent of neocortical growth. As well as apically localised radial glial cells (RGCs) that comprise the stem cell compartment, various populations of basal progenitors (BPs) exist – including basal RGCs, with both self-renewal and proliferative capacity, and more restricted progenitors. The stem cell-like properties of RGCs are linked to the fact that these cells are connected to the basal lamina, from which they receive proliferative signals via integrins. Now, Denise Stenzel et al. investigate in rodents the role of integrin α_vβ₃ in regulating the proliferative capacity of BPs (p. 795). They find that activation of this integrin induces BP proliferation both in hemisphere culture and in vivo, promoting proliferative division at the expense of neurogenic division. Moreover, they show that the α_vβ₃ ligand thyroid hormone also regulates BP proliferation via this integrin – providing pro-proliferative signals to progenitor cells that are not connected to the basal lamina.

Tracing the origin of epidermal immune cells

Langerhans cells (LCs) are antigen-presenting cells of the epidermis, and play a key role in detecting pathogens in the skin and coordinating the immune response. However, the precursors of LCs during embryonic development are poorly characterised, particularly in humans. Here (p. 807), Adelheid Elbe-Bürger and colleagues analyse the characteristics of early LC precursors in human first-trimester foetal skin, and explore the potential of different populations of haematopoietic precursors to colonise the developing epidermis. They find an unexpected diversity in LC precursors in terms of cell-surface markers, contrasting with the homogeneous adult LC population. The authors then used in vitro skin equivalent cultures to test the ability of different cord blood-derived precursor populations to colonise the epidermis and differentiate as LCs. Various precursor subtypes show LC potential, and the data suggest that the skin equivalents produce those signals necessary to direct LC differentiation. Together, these data suggest a heterogeneous origin for human embryonic LC precursors during early stages of development.

How to make a heart: insights from machine learning

The Drosophila heart provides a relatively simple system for the analysis of gene regulatory networks (GRNs), as it comprises just two cell types – contractile cardial cells (CCs) and non-muscle pericardial cells (PCs). Moreover, many transcription factors (TFs) that regulate Drosophila heart development have been identified and shown to play conserved roles in mammals. On p. 878, Alan Michelson and co-workers take a machine learning approach to identify new cardiac enhancers. The methodology, which integrates chromatin immunoprecipitation data with TF motif mapping, is highly successful at predicting enhancers that drive expression in cardiac cells, including PC- or CC-specific enhancers. Among the highly over-represented TF motifs in putative cardiac enhancers are motifs for the Myb and Su(H) TFs; the authors show that Myb regulates progenitor cell division, while Su(H) controls the PC/CC lineage decision. This work demonstrates the utility of machine learning to identify novel players regulating organ formation, and to piece together the GRNs underlying cell fate specification.

Controlling meristem activity

The shoot apical meristem (SAM) of higher plants contains the stem cell population that contributes to all above-ground organs. During vegetative growth, leaf primordia emerge from the periphery of the SAM, and the SAM transitions to an inflorescence meristem to initiate the reproductive phase. The WUSCHEL transcription factor specifies stem cell fate, and hence controls the size and activity of the SAM. A gene network involving the CLAVATA signalling pathway, the microRNA miR166g and HD-ZIPIII transcription factors is responsible for regulating WUSCHEL levels. On p. 830, Leor Eshed Williams and colleagues add another layer to this regulatory system, defining a role for the ERECTA receptor kinase in restricting WUSCHEL expression. Plants overexpressing miR166g and carrying a mutation in ERECTA display a massively enlarged SAM, disrupted phyllotaxis patterns and defects in floral meristem formation. ERECTA acts independently of the CLAVATA system, and although the mechanisms by which it functions are not fully clear, this work adds another important player to the complex regulatory network underlying meristem activity.

Mcr connects cell connections with innate immunity

The Drosophila Mcr protein is a member of the thioester protein (TEP) family of proteins, which includes key regulators of innate immunity. Mcr is an unusual member of this family, possessing a putative transmembrane domain and lacking a key residue in the thioester motif. It has, nevertheless, been shown to be involved in phagocytic uptake in cultured Drosophila cells, although its putative immune functions have not been assessed in vivo. Two papers, from Stefan Luschnig and colleagues (p. 899) and Robert Ward and colleagues (p. 889), now identify Mcr as a new component of septate junctions (SJs), the invertebrate equivalent of tight junctions that form the paracellular barrier in epithelia.

Both studies identify lethal EMS mutations inMcr in independent genetic screens, finding mutant phenotypes typical of SJ components. Consistent with a putative role in SJ formation, the protein colocalises with other SJ proteins at the lateral membrane. They further find that Mcr localisation is dependent on core SJ components and that, conversely, SJ proteins are mislocalised in Mcr mutants. At the morphological and ultrastructural level, SJs are disrupted in the absence of Mcr, and functional assays demonstrate that Mcr is required to form an effective paracellular barrier. As well as identifying a new SJ protein essential for barrier integrity, these two studies suggest an intriguing link between SJs and innate immunity. The epithelial barrier represents the first line of defence against pathogen invasion, andDrosophila haemocytes are known to undergo an epithelialisation-like process when encapsulating pathogens in the haemolymph. The identification of Mcr as a protein involved in both SJ formation and innate immunity now provides a molecular connection, and opens up new avenues for investigating potential functional links, between these two seemingly disparate processes.

PLUS…

Cytonemes as specialized signaling filopodia

Thomas Kornberg and Sougate Roy review the evidence that establishes a fundamental and essential role for cytonemes as specialized filopodia that transport signaling proteins between signaling cells. See the Primer article on p. 729

Pax genes: regulators of lineage specification and progenitor cell maintenance

Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Here, Judith Blake and Melanie Ziman review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. See the Primer article on p. 737

How to make an intestine

James Wells and Jason Spence review how recent advances in developmental and stem cell biology have made it possible to generate complex, three-dimensional, human intestinal tissues in vitro through directed differentiation of human pluripotent stem cells. See the Primer on p. 752

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Having celebrated its 120th anniversary last year, the Woods Hole embryology course is back in 2014!

The course will consist of 6 intense weeks of lectures and laboratory work, from the 7th of June to the 20th of July, and applications are open to graduate students, postdoctoral fellows and senior researchers seeking a broad view of developmental biology and the methodologies used to study it. Deadline for application is this Friday, the 7th of February.

Check out the course’s website, as well as the application page, for more details.

You can read about last year’s course here on the Node:

– Exploring Embryology at the Woods Hole MBL, by Lara Linden

– Discovery at the MBL, by Kazutaka Hosoda

– Six weeks in Woods Hole, by Alice Accorsi

Also read our interview with one of the current co-directors of the course, Prof. Alejandro Sánchez Alvarado, and check last years’ image competitions for a taster of the beautiful images produced by the attendees of the course (round 1, 2, 3 and 4).
 
 

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Until last year, I was a bioinformatician post-doc in the laboratory of Prof. Richard Harvey, at the Victor Chang Cardiac Research Institute in Sydney. My project consisted of deciphering the regulatory network that controls heart development and how this network might be perturbed in disease conditions, such as congenital heart disease (which in Australia affects one in a hundred newborn babies). For this, we used a mouse cell line (HL-1 cells) which was a great system to rapidly obtain all the genome-wide information that we needed for the project, but had its limitations since it is an adult cell line that is cultured in vitro. In the meantime, the laboratory of Dr. Eileen Furlong at EMBL Heidelberg in Germany published a new method, BiTS-ChIP-seq (Bonn et al., 2012), that allows to obtain genome-wide information from tissue specific cell-types in vivo. Using this method in the developing zebrafish, in a transgenic line that specifically labels heart nuclei (cf image), would be the perfect experiment to gain insight into the nature of this gene regulatory network in vivo.

When I started to plan the experiment, I was daunted by the detailed published protocol due to its length and complexity, but mainly due to my own limitations- it included many techniques that I had never performed before. My time was limited, as my post-doc was ending at the end of the year. The quickest way to get these experiments going was to get “hands-on” experience on this protocol. These are the times when I miss Europe, where I could just hop on a train and visit a large number of diverse laboratories nearby. Yes, I am in Australia, and “popping-in” to visit any European laboratory involves a 24-hour flight (one way) and lots of $$. Fortunately, our grants management officer encouraged me to apply for a Development travelling fellowship from the Company of Biologists to support this visit. Thanks to this fellowship, I had the hands-on experience to learn the protocol and its “tricks” that I wanted, which probably saved me months of trials to get it right.

Far beyond the technical knowledge that I gained, receiving the fellowship also had great repercussions on my career path. At the time I was doing this work, I was also in the process of looking for independent positions and writing grants to fund it. I submitted a proposal to the Australian Research Council that included the BiTS-ChIP-seq experiments, in collaboration with Dr. Furlong’s laboratory. An important criterion for the grant was to provide evidence of this collaboration, ideally by showing co-authored publications. Since we had not published together at that time, the visits to Dr. Furlong’s laboratory definitely testified for the feasibility of these experiments in my hands, which was essential for the success of the grant.

In summary, receiving the Development travelling fellowship allowed me to save time on experiments, strengthen my collaborations around the world, and help to win my first grant to start my lab at the Australian Regenerative Medicine Institute in Melbourne.

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January was a busy month on the Node, particularly our jobs page, which included several new postdoctoral positions, as well as PhD studentships, group leader and technician positions.

Here are some of the other highlights:

Research:

– Yan Yun wrote about his recent Development paper examining the origins of aneuploidy by tracking chromosomes and their kinetochores in oocytes from young and aged mice.

– Oguz discussed the development of Raeppli, a new technique that allows whole tissue labelling in Drosophila.

– and Christele’s stem cell image choice this month is from a Cell Reports paper showing that the junctional adhesion molecule JAM-A is essential for the survival and growth of the cancer stem cells found in glioblastoma.

Science life:

– Erin kicked off our model organism series in 2014 with her post ‘A day in the life of a Parhyale lab’– make sure to read it to learn all about using beach hoppers in developmental biology.

– Máté discusses the experience of returning to his home country Hungary to establish his own lab after a PhD and postdoc abroad.

– And Sonia, a postdoc at the National Centre for Biological Sciences in India, wrote about her recent collaborative visit to a lab in California.

Also on the Node:

– If you are keen in writing on the Node but have never blogged before, we collated a list of handy tips to get you started.

– We had a look at our stats to find the top posts of 2013.

– And there is less than a month left to participate in our outreach competition!

Happy reading!

 Writing image: Wellcome Library, London

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Physics and Biology were the media darlings last week. Earlier, one of my favorite physicists Professor Stephen Hawking claimed through his paper that there are no black holes! Well… later I realized he actually insist in calling it with different name, “Metastable bound states of the gravitational field”!!! I know I am not meant to explore the nature of black holes. Nevertheless, While I was contemplating over the yes-or-no event horizon, there came hey-remember-you-are-a-biologist kind of reminder articles in Nature and makes a sensation. I first read about it from a random free newspaper on London Tube. Now you know how quickly it hit the media!

By now, most of people who work in the research field which uses key word “stem cells” should be aware of these two articles. So me not going into much details. Apparently, Haruko Obokata and Charles Vacanti’s team has done amazing job in showing a new method to derive iPS-like cells (as Yamanaka calls it). The method involves exposing the cells to stress, like comfortable acidic pH. And the rest of the story is well known.

Now, the lesson for me from these two articles is not only how I can reprogram cells in a new way but also how an alternative thinking can lead to breakthrough discoveries. Most of the scientists often plunged into narrow topics that often restricts to think outside the lab. As the lead author says, the original idea occurred to her when she thought about plants how they regenerate missing parts when it get chopped off. Obviously plants do not need to overexpress Yamanaka factors-like factors or any genetic manipulation to regenerate. In plants, mostly the regeneration is induced by stress. By inspired by this, the authors tried various stress applications including to squeeze the cells through narrow capillary pipettes (of course, without killing) and see if it could make the cells to do something different. And the ingenious idea of dipping cells in low pH worked out! Inspirations all around us, we need to keep eyes open, a bit wider.

Lateral thinking is vital in biology and science in general, I say!

This post is also available in our lab blog – wattlab blog. Please visit for more interesting topics and discussions.

Further reading

S. W. Hawking (2014) Information Preservation and Weather Forecasting for Black Holes. Preprint at http://arxiv.org/abs/1401.5761.

Obokata et al., (2014) Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature. 505, 641–647.

Obokata et al., (2014) Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. Nature. 505, 676–680.

(3 votes)

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This two-week course combines lectures and practical sessions to leading edge technologies and questions in stem cells biology in the context of organogenesis and regeneration in different organisms.

This course is intended for research scientists and PhD students who already have laboratory experience and a good knowledge (equivalent to a Master level) in developmental and cell biology. It provides a wide scope of how stem cells have adopted strategies to effect organogenesis and regeneration in different organisms.

The practical part covers methods and techniques that will allow participants to reproduce state of the art technologies in their own research activities. Leading-edge approaches in identification, derivation, analysis and imaging of stem cells will be presented. Distinct model systems and organisms have been chosen to expose the participants to the advantages and challenges in each paradigm and to provide added insights into the biology of stem cells. The models include mouse, zebrafish, Drosophila, and ES and iPS cells.

Lectures will be presented by selected speakers who investigate not only stem cells but also use innovative technologies.

Networking and discussion opportunities will be enhanced by the convivial formal and ad hoc discussion sessions in the teaching facilities.

For more detailed information the program of the 2013 course can be dowloaded (at http://www.pasteur.fr/sites/www.pasteur.fr/files/programme_ascb.pdf); some topics and practical sessions might change from year to year, without altering the general frame and means of the course.

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Of all the types of stem cells, there is a kind than can be a lot more scary than beautiful: the cancer stem cell. Although the concept of cancer stem cell is still controversial among the scientific community, it is of great medical interest to further understand these cells so that we develop better strategies to tackle them. Cancer stem cells are described as cells with regular stem cell characteristics, they can – self renew (make identical copies of themselves) and – differentiate (give rise to multiple cell types). However, contrary to normal stem cells, they can also give rise to malignant tumors.

Since normal stem cells and cancer stem cells share many characteristics, it is a major challenge to identify molecules (also called markers) that are specifically located on malignant cells and not healthy ones, or mechanisms that are important for the function of malignant cells but not for the function of healthy ones.

In a recent study published in Cell Reports, Lathia and colleagues showed that the junctional adhesion molecule JAM-A was essential for the survival and growth of the cancer stem cells found in glioblastoma, a type of brain tumor; but dispensable for normal brain stem cell function.

In this image, you can observe cancer stem cells obtained from a patient’s glioblastoma and grown in-vitro. In green is JAM-A protein, in red is α-6 integrin protein, and in blue are cell nuclei. Overlap of the green and red (yellow) shows that cells that express α-6 integrin also express JAM-A. Since α-6 integrin was shown to be a marker for glioblastoma cancer stem cells in a previous study by the same group, this picture confirms that JAM-A, being located on the same cells as α-6 integrin, can also be used as a marker for glioblastoma cancer stem cell.

Further down in the study, Lathia and colleagues show that JAM-A is almost undetectable on healthy brain stem cells. Also, blocking of JAM-A reduces cancer stem cell growth but does not affect the growth and function of other healthy brain stem cells. Altogether, since JAM-A is specifically important to glioblastoma cancer stem cell function, it could a promising therapeutic target for treating this type of cancer, making those stem cells a little less scary.

Lathia, J. D., Li, M., Sinyuk, M., Alvarado, A. G., Flavahan, W. A., Stoltz, K., Rosager, A. M., Hale, J., Hitomi, M., Gallagher, J. et al. (2014) ‘High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor’, Cell Rep 6(1): 117-29.

doi: 10.1016/j.celrep.2013.11.043

(2 votes)

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Young Group Leader Positions

in Stem Cell Biology

The Institut Pasteur (Paris, France) announces an international call for candidates wishing to establish independent research groups. The recruitments are part of the Revive Laboratory of Excellence (LabEx) programme on “Stem Cells and Regenerative Biology and Medicine”. Candidates will be integrated into the cutting edge interdisciplinary environment provided by the Department of Developmental & Stem Cell Biology. Candidates specializing in the field of stem cells in the context of developmental and cell biology, genetics, epigenetics, regeneration, translational research and ageing are encouraged to apply.

To be eligible, candidates must have defended their PhD on or after June 15, 2006 (women with children are eligible up to 11 yrs after their Ph.D). Successful candidates will be appointed as head of a group of up to 6 people for a period of 5 years. The budget (up to €1,500,000 over 5 years) includes the salary for the group leader, a three-year postdoctoral position, a technician’s position, part-time secretarial assistance, a substantial contribution to running costs and equipment, and access to on-campus facilities including state-of-the-art technology core facilities. Candidates should send their formal applications by E-mail to the Director of Scientific Evaluation, Prof. Alain Israël, at the Institut Pasteur (g5revive@pasteur.fr).

Application deadline: June 15, 2014

Short-listed candidates will be contacted for interview to be scheduled for beginning of September 2014 and recruitment decisions announced by October 2014. Further information on the Revive program can be found at http://www.pasteur.fr/revive

Applicants should provide the following (in order) in a single pdf file:

1. A brief introductory letter of motivation, including the name of the proposed group. Candidates are encouraged to contact the coordinator of the Revive programme Shahragim Tajbakhsh (shaht@pasteur.fr).

2. A Curriculum Vitae and a full publication list.

3. A description of past and present research activities (up to 5 pages with 1.5 spacing; Times 11 or Arial 10 font size).

4. The proposed research project (up 10 pages with 1.5 spacing; ; Times 11 or Arial 10 font size).

5. The names of 3 scientists from whom letters of recommendation can be sought, together with the names of scientists with a potential conflict of interest from whom evaluations should not be requested.

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An exciting opportunity exists for a highly motivated individual to join the Epidermal Development Laboratory in the Department of Medicine. The group has an interest in understanding the mechanisms underpinning epidermal development and homeostasis.

As the Research Officer or Senior Research Officer, you will investigate the genetic pathways which regulate vertebrate craniofacial development, with a focus on Grhl2, one of the genes responsible for facial skeletal development. The project will involve molecular and cellular experiments, histology and animal handling.

Any Enquiries to

Dr Sebastian Dworkin, Senior Research Fellow, +61 3 9903 0072

For more details visit : http://www.seek.com.au/job/25919366

(1 votes)

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IIMCB (http://iimcb.gov.pl) is the top-ranked Polish research institute in the field of biology.

The institute provides cutting-edge equipment and facilities, including a newly established zebrafish facility, bioimaging facilities, strong bioinformatics cluster, and structural biology. The IIMCB is committed to provide a supportive and inclusive work environment.

A full time technical assistant position is available starting from April 2014 for a highly motivated researcher in the laboratory of Zebrafish Developmental Genomics. This position is funded by the EC FP7 grant “FishMed – Fishing for medicines and their targets using zebrafish models of human diseases” and will be available for 2 years with the possibility of extension.

The group will apply state-of-the-art genomics approach to study the gene regulatory networks regulating embryonic development in zebrafish. Responsibilities include providing technical expertise to support research (e.g. general molecular biology and biochemistry techniques, FACS, in situ hybridization, microscopy, zebrafish embryo techniques), and general management of the laboratory which include keeping track and purchasing of laboratory stock reagents or equipment.

Position requirements

The candidate should hold a first degree in biology or other equivalent fields and demonstrated laboratory experience with expertise in basic molecular biology and biochemistry techniques including nucleic acid and protein isolation, molecular cloning, real-time PCR, and western blot among others. Experience with FACS, preparation of next generation sequencing libraries, and working with zebrafish is highly desirable but not essential. The ideal candidate should be self-motivated and have excellent organisational skill and attention to detail. He/she must be capable to work as part of a team and possess good communication and interpersonal skills.

The successful candidate is expected to start work by 1st of April, 2014. We offer a competitive monthly salary which is adjusted to the cost of living in Warsaw.

Please forward your complete application including a CV, a motivation letter, and the names of two referees to cwinata[at]iimcb.gov.pl by 15th of March, 2014.

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