(This interview originally appeared in Development.)

The Sainsbury Laboratory at the University of Cambridge is a new research institute that aims to achieve an integrated understanding of plant development. Its Associate Director is the new plant Editor of Development, Ottoline Leyser, who is also Professor of Plant Development at the University of Cambridge. We recently caught up with Professor Leyser and asked her about the Sainsbury Laboratory and about her own research interests.

When did you first become interested in plant development?

To me, plant development has always been much more interesting than animal development, because of its plasticity. In plants, the body plan is incredibly flexible: one genotype can occupy an extraordinary range of phenotype space. I’ve always thought that was just amazing.

I did my undergraduate degree here in Cambridge, in the Genetics Department, not in plant science. We had this absolutely fantastic interdepartmental development course that was taught by John Gurdon, Peter Lawrence and many other wonderful people. It was very striking, the contrast between what was happening in animal development, which was being transformed by Drosophila genetics, by Christiane Nüsslein-Volhard, Eric Wieschaus and others, and what was happening in plants: despite the long tradition of genetics in plants, developmental genetics somehow hadn’t really taken off. But in the final year of my undergraduate degree, there were the first hints of Arabidopsis as a model organism, driven at least in part by Elliot Meyerowitz, who is now the inaugural director here at the Sainsbury Laboratory. So, there was suddenly a very exciting opportunity to push things ahead in plant development using developmental genetics. I started looking for a PhD position in an Arabidopsis lab and, fortunately for me, Ian Furner had just arrived back from the USA clutching some Arabidopsis seed in a tube, so I stayed in Cambridge and did my PhD with him, studying meristem mutants in Arabidopsis.

What are you working on at the moment?

I’m working on the role of plant hormones in integration of the endogenous and environmental signals that control the plant body plan. We’re looking principally at shoot branching control and are trying to understand how every individual axillary bud on the plant makes a decision about whether to activate or not, depending on multiple inputs. It’s really a question of signal integration.

You’ve recently moved your lab from York to Cambridge to set up the new Sainsbury Laboratory. How did the lab move go?

It’s still an ongoing process. We’re pioneers down here, who have had to deal with a very fabulous but nonetheless brand new and, at the time, unfinished building. But now that the first results from experiments carried out in the new lab are coming in it’s very exciting. Meanwhile, there’s still a core of people in York, partly because some people didn’t want to move and partly because we’re in the middle of a rather long-term ten-generation Arabidopsis experiment, which I didn’t want to move.

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Here are the highlights from the current issue of Development:

The skin-healing touch of Lhx2

Skin repair after injury involves the recruitment of undifferentiated progenitor cells from nearby hair follicles (HFs) into the regenerating epidermis. The bulge and the secondary hair germ of HFs contain distinct populations of epithelial stem cells, and now Vladimir Botchkarev and co-workers reveal that the Lim-homeodomain transcription factor Lhx2 differentially regulates these populations during wound healing (p. 4843). They show that, in mice, most of the cells that proliferate in response to skin injury in the HF bulge and secondary hair germ express Lhx2. Wound re-epithelisation is retarded in Lhx2^+/– mice compared with wild-type mice, they report, whereas the onset of active hair growth in HFs near to the wound is accelerated. Other experiments indicate that Lhx2 promotes wound re-epithelisation by upregulating Sox9 and Tcf4 expression in the bulge cells while simultaneously inhibiting HF cycling by downregulating Lgr5 expression in the secondary hair germ. Thus, Lhx2 is a key regulator of the differential response of HF stem cells during epidermal regeneration after injury.

Nanog: an ancient reprogrammer

The establishment of pluripotency during mouse embryogenesis and during the reprogramming of somatic cells is dependent on the homeodomain-containing transcription factor Nanog but, puzzlingly, compared with other pluripotency-associated genes, Nanog is poorly conserved among vertebrates. Here (p. 4853), José Silva, Filipe Castro and colleagues investigate whether Nanog orthologues can orchestrate pluripotency in Nanog^–/– mouse somatic cells. Surprisingly, the researchers report that mammalian, avian and teleost Nanog orthologues all reprogramme mouse Nanog^-/- somatic cells to full pluripotency, despite sharing as little as 13% sequence identity with mouse Nanog. Moreover, they identify two unique residues in the DNA recognition helix of the Nanog homeodomain that are important for reprogramming and show that the Nanog homeodomain is sufficient to enable naive pluripotency in Nanog^–/– somatic cells. These functional studies, together with genome analyses, suggest that Nanog is a vertebrate innovation and that its reprogramming capacity resides within a unique DNA-binding domain that probably appeared at least 450 million years ago in a common ancestor of vertebrates.

R-spondin to developmental angiogenesis

During embryogenesis, two sequential processes form the vasculature: during vasculogenesis, endothelial progenitor cells form the primary vascular bed; subsequently, during angiogenesis, additional vessels sprout and grow from pre-existing vessels. Here, Aniket Gore, Brant Weinstein and co-workers identify a novel signalling pathway that promotes developmental angiogenesis in zebrafish (see p. 4875). Their first clue to this pathway came when they identified a mutation in R-spondin1 (rspo1) during a forward-genetic screen for angiogenesis-deficient zebrafish mutants. Embryos lacking rspo1 or its receptor kremen form primary vessels, they report, but do not undergo angiogenesis. R-spondin is a Wnt signalling regulator and, by functionally manipulating different members of the Wnt pathway, the researchers show that canonical Wnt signalling is required downstream of rspo1 for sprouting angiogenesis. Finally, they show that Vegfc/Vegfr3 signalling mediates the pro-angiogenic effects of Rspo1/Wnt signalling and that all four proteins are expressed by the endothelium during sprouting angiogenesis. Together, these results suggest that Rspo1-Wnt-Vegfc-Vegfr3 signalling is an endothelial-autonomous permissive cue for developmental angiogenesis.

Compartmentalised PKA, cilia and hedgehog signalling

Protein kinase A (PKA), a conserved negative regulator of the hedgehog (Hh) signalling pathway, generates the transcriptional repressor form of Gli3 in the absence of Hh in mice. Now, Kathryn Anderson and colleagues show that the total loss of PKA activity in mouse embryos leads to a completely ventralised neural tube and mid-gestation lethality (see p. 4921), which indicates that the sonic hedgehog (Shh) signalling pathway is maximally activated in all neural progenitors in the absence of PKA. Notably, genetic experiments indicate that the principal function of PKA in the neural plate is to prevent Gli2 activation of Shh targets. Other experiments reveal that Hh pathway activation in PKA mutants depends on cilia, that PKA is localised at the basal body of primary cilia, and that Gli2 levels are increased at the tips of cilia of PKA-null cells. The researchers propose, therefore, that two separate cilia-associated compartments determine the accessibility of Gli proteins to PKA and thus the activity of the Shh pathway in vertebrates.

miR-124 notches up neural development

MicroRNAs (miRNAs) play crucial roles in development. miR-124, for example, is abundantly expressed in the mouse brain and is necessary for proper nervous system development, but how it drives neuronal differentiation is unclear. To remedy this lack of understanding, Robert Zeller and colleagues have comprehensively analysed miR-124 expression, function and target genes in the ascidian Ciona intestinalis (see p. 4943). They report that miR-124 interacts with several signalling pathways that are involved in nervous system development. In particular, they show that a feedback interaction between miR-124 and Notch signalling regulates the epidermal-peripheral nervous system (PNS) fate choice in tail midline cells. Thus, Notch signalling silences miR-124 in epidermal midline cells, whereas in PNS midline cells miR-124 silences Notch, Neuralized and the Ciona Hairy/Enhancer-of-Split genes. Moreover, miR-124 also shapes neuronal progenitor fields by downregulating non-neural genes including 50 Brachyury-regulated notochord genes and the muscle specifier Macho-1. Overall, these results indicate that miR-124 plays a multifaceted role in cell lineage specification during nervous system development.

Spotlight on adipogenesis

Adipose tissue (a specialised energy storage structure) is the only tissue that can change its mass substantially during adult life. It does this through changes in the size of its constituent cells (adipocytes) and through the de novo generation of cells. Unfortunately, given the obesity epidemic, adipocyte development in vivo is poorly understood but, here, Gou Young Koh and colleagues provide new insights into adipogenesis by analyzing the postnatal development of epididymal adipose tissue (EAT) in mice (p. 5027). They show that EAT is generated from non-adipose tissue during the first 14 postnatal days of development and that this non-adipose tissue is initially composed of multipotent progenitor cells (possibly including adipoblasts) that lack adipogenic differentiation capacity in vitro. By postnatal day 4, however, progenitor cells isolated from EAT can form adipocytes if they are provided with cell-to-matrix and cell-to-cell contacts. Finally, the researchers show that impaired angiogenesis in postnatal mice interferes with adipogenesis. Thus, they conclude, cues from cellular and matrix components, together with appropriate angiogenesis, are required for adipose tissue development.

Plus…

Evolutionary crossroads in developmental biology: amphioxus

As part of the Evolutionary Crossroads in Developmental Biology series, Bertrand and Escriva introduce amphioxus and discuss how studies of this model have informed us about the evolution of vertebrate traits.

See the Primer article on p. 4819

An interview with Ottoline Leyser

The Sainsbury Laboratory at the University of Cambridge is a new research institute that aims to achieve an integrated understanding of plant development. Its Associate Director is the new plant Editor of Development, Ottoline Leyser, who is also Professor of Plant Development at the University of Cambridge. We recently caught up with Professor Leyser and asked her about the Sainsbury Laboratory and about her own research interests.

See the Spotlight article on p. 4815

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(This interview originally appeared in Development.)

Gordon Keller is Director of the McEwen Centre for Regenerative Medicine at the University Health Network in Toronto, Canada. His research applies concepts from developmental biology to the investigation of the lineage-specific differentiation of mouse and human embryonic stem (ES) cells. He became an Editor of Development in 2011, and recently we asked him a few questions to find out more about him and his research.

Who or what inspired you to study science?

I was always curious, and I found a scientific career to be one that allowed me to explore my curiosity.

What sparked your interest to work on the directed differentiation of stem cells?

That was a seminar by Rolf Kemler in 1984. I was in the Basel Institute for Immunology – I had arrived there about a year earlier – and Rolf came to the institute and showed us these beautiful, huge cystic embryoid bodies, in which you could see blood and vascular structures and beating heart cells. Knowing that you could make that from an ES cell piqued my interest and I decided to pursue research in this topic.

What made you return to Canada after having worked in Switzerland and the USA?

There were several things. First, there was an opportunity here to direct the McEwen Centre for Regenerative Medicine. Canada, and Toronto in particular, has a very strong scientific community but also a very strong stem cell biology community. And I am Canadian, and felt it would be a wonderful opportunity to return home and spend part of my career here.

What has been the biggest surprise that you have come across in your research?

I don’t know whether you would call it a surprise, but I have been amazed at the speed at which stem cell research has progressed. We have worked for years at differentiating mouse ES cells, and, although people were interested, it was always somewhat on the back burner. Then the discovery of human ES cells and induced pluripotent stem (iPS) cells transformed the field, and the kind of work we do has now become more mainstream. In a nutshell, I don’t know if I have been surprised by any particular finding so much, but what I find most remarkable is the evolution of the field and seeing it change almost on a weekly basis.

Given these ongoing changes, where do you see the field move next?

I think the biggest challenge that we have is to find a way to get the cells that we make in a dish to integrate into adult tissue and function. We are certainly making components of human tissues and organs, but to date there is not much evidence yet that they are functional, so I think the next hurdle – the big challenge before we can really make an argument that these are clinically relevant cells – is to find out whether in vitro differentiated cells can integrate into adult organ function.

How does developmental biology inform in vitro differentiation?

Developmental biology is the basis of all we do. For the last eight years, we have looked closely at concepts from developmental biology; for example, the pathways that control lineage specification in the early embryo. We initially applied these concepts to mouse ES cells, and more recently to human ES cells. Using knowledge from developmental biology has provided us with a very informed way to develop strategies and protocols that are both robust and efficient.

What is the role of Development within your field?

Many of the key papers that we look at to inform our work have been published in Development, and we have published a lot of our own ES cell work in the journal as well. At times, publishing our work has been challenging, I must say, because when we started it was a new system and a lot of people didn’t believe that cells in a dish could recapitulate development. But Development was very supportive and allowed us an avenue to publish our research.

Is there a particular type of in vitro differentiation paper that you would encourage people to submit to Development?

Absolutely. I would like to see ES cell differentiation papers coming to Development. This could include papers that use the system to study aspects of development that are very difficult to study in an embryo, and there are many examples of that. As we are starting to move from animal models towards human biology, ES cell differentiation is going to be the model for human developmental biology, and I would be delighted if the journal could stake a claim to human developmental biology.

If you were not a scientist, what career would you have chosen?

I have no idea. In fact I’m not sure that I had a priority to start with. I didn’t grow up saying ‘I want to be a scientist’, but rather I followed a path where my thoughts were along the lines of ‘I find this interesting, I’ll pursue it somewhat more’.

(2 votes)

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The European Court of Justice has today announced a landmark decision banning patenting of inventions based on embryonic stem cells. Several senior stem cell biologists have expressed their concern that the verdict, which is legally binding for all EU states, will drive development of stem cell therapies outside Europe.

You can read more about the case on eurostemcell.org here: http://www.eurostemcell.org/story/european-court-bans-stem-cell-patents. We’d love to hear your views – why not post a comment on our site?

And while you’re visiting eurostemcell.org, have a look around! We’ve been busy over recent months and we’ve got loads of new content: Interviews with scientists, fact sheets and new educational tools in our stem cell toolkit, to name but a few.

(2 votes)

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Teaching Tools in Plant Biology is an online educational resource published by The Plant Cell and the American Society of Plant Biologists.  Each Teaching Tool includes a set of about 100 PowerPoint slides, a review article suitable for undergraduates with hyperlinked reading lists, and a teaching guide that includes learning objectives and discussion questions. Each article is peer-reviewed and incorporates broad introductory materials as well as some in-depth analysis of key experiments, so can be tailored for use with a variety of students, and each is updated annually. Topics include Leaf Development, Epigenetics, Phytohormones, Why Study Plants and Genetic Improvements in Agriculture. Teaching Tools are available to personal or institutional subscribers of The Plant Cell, but the first six articles, including Leaf Development and Epigenetics, do not require a subscription. We also have a FaceBook page on which we highlight timely topics of interest to teachers of plant development, genetics, molecular and cell biology and physiology. Please have a look and use any materials you like. We’re always happy for feedback! Send comments to mwilliams@aspb.org.

(6 votes)

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What would you do if you were given $500,000 to fund your research for five years, with no strings attached –– no proposals to write, no progress reports to submit? If you were one of the recently announced recipients of the prestigious MacArthur fellowship you would be giving this question some serious thought.

Every year since 1981 the John D. and Catherine T. MacArthur Foundation recognizes exceptionally creative individuals by awarding them with $500,000 “genius grants”. According to the press release published on September 20th “MacArthur fellowships come without stipulations or reporting requirements and offer fellows unprecedented freedom and opportunity to reflect, create, and explore. All [fellows] were selected for their creativity, originality, and potential to make important contributions in the future.”

To be considered for the MacArthur fellowship requires a nomination.  However the identities of the nominators as well as the selection process are kept in complete secrecy.  Those who are selected for the award find out through an “out of the blue” phone call from the foundation two weeks prior to the official announcement. This year’s 22 recipients include a musician, a poet, a historian, an economist, a radio producer as well as 10 scientists.  Among them is Yukiko Yamashita a developmental biologist and assistant research professor at the University of Michigan who studies the mechanisms regulating stem cell division in the context of unperturbed tissue anatomy –– adult testes.

Getting the Call

When Yukiko received the phone call informing her about being selected and asking her asking her not to discuss it with anyone except her spouse until the official announcement, she had a hard time believing that it was not a scam. “I called my husband right after I hung up my phone call with the foundation and [he] seriously warned me that ‘if you get a second phone call asking your bank account and pin number, so that they can transfer the award money, don’t give it to them.’”

They did not ask for her bank info but did want to bring a production crew to her lab to film an interview for the foundation’s website.  “I had to ask the director of my institute if the production crew can come into the building to film me before the press release. We seriously have to worry about some activists against research blowing up the building. I didn’t want to be the stupid assistant professor who believed they are awarded a MacArthur ended up with destroying the entire institute.” When the names of this years MacArthur fellows were finally announced publicly Yukiko felt more relieved than ecstatic.

Yukiko completed her undergraduate and doctoral studies in Japan, at Kyoto University, followed by postdoctoral training with Margaret Fuller in the Department of Developmental Biology at Stanford University. In 2007 she established her own lab as an assistant research professor at the University of Michigan Medical School.

Choose Your Centrosome Wisely

Her current research, which has won her the recognition from the MacArthur foundation, combines cell and developmental biology and is focused on investigating molecular and cellular mechanisms governing stem cell behavior, using the Drosophila male germline stem cells (GSCs) as a model. Her lab is investigating how stem cell division is regulated and how different stem cell populations interact to maintain tissue stability.

During her time at Stanford, Yukiko made the discovery that the centrosomes of Drosophila male GSCs are non-randomly segregated during asymmetric division –– the older “mother” centrosome remains with the stem cell while the newly replicated “daughter” centrosome is inherited by the differentiating cell.

The GSCs in Drosophila reside in a niche composed somatic support cells called hub cells and cyst stem cells. GSCs attach to the support cells at their apical side and during cell division orient the mitotic spindle along the apical-basal axis.  The cells still attached to the hub after cell division maintain a stem fate, while the daughter cell, displaced from the hub, differentiates.

“Its been known for quite a long time in the cell biology field that mother and daughter centrosomes are a little different from each other. The newborn centriole in the centrosome takes more than one cell cycle to get fully mature,” says Yukiko. As the centriole matures it accumulates structures called subdistal appendages, which serve to anchor the microtubles forming the spindle. Mature centrosomes therefore have a stronger ability to anchor microtubules. “Because of this difference the mother centrosome always has higher microtubule nucleating capacity.” In fact Yukiko’s found that the mother centrosome is anchored by microtubules at the apical pole of the cell, near the hub. “That is why, we are guessing, the mother centrosome can stay close to the hub cells all the time.”

However this mechanism is not universal to all stem cells.  “In Drosophila neuroblasts, every single cell cycle the mother centrosome gets inactivated and the daughter centromosme gets activated and so, unconventionally, the daughter centrosome has higher [microtubule organizing center] MTOC activity. In the end the stem cell ends up inheriting the daughter centrosome all the time.” The reasoning for this switching is not known, however the trend is that the centrosome with higher MTOC activity is inherited by the stem cell.  “In one case, germ line stem cells maintain higher MTOC activity on the mother centrosome, but in the Drosophila neuroblasts they make daughter centrosome with high MTOC activity. Why this is happening we don’t know. But once you have high MTOC activity it looks like that’s going to the stem cell.”

How Do Chromosomes Fit Into the Picture?

Following Yukiko’s discovery about the non-random segregation of centrosomes other scientists in the field speculated that it might serve as a mechanism to selectively segregate chromosomes, perhaps keeping the original strands in the stem cell as proposed by the immortal strand hypothesis. Yukiko, however, was not convinced that this was the case and thought that a thorough analysis was required to prove or disprove the hypothesis –– something that she felt was lacking in some studies.

“We thought we really should address this question in our system, in which we can directly test this idea,” she says.  In early 2011 Yukiko’s group published a paper in the Journal of Cell Science reporting that the chromosomes of GSCs, unlike the centrosomes, are randomly segregated.  “I’m glad that we published this paper because I think [among] the immortal strand hypothesis papers, some are really good and the data appears really convincing, but some others are not really excluding alternative possibilities or different interpretations. I really wanted to propose some rigorous way of testing it. I’m not saying that the immortal strand [hypothesis] is not correct, but then to make it right, you have to examine every single possibility.”

Since that publication, a the graduate student pursuing this line of research in her lab has examined the segregation of each individual strand for all the chromosomes and  found that at this level of resolution only a small subset of chromosomes are selectively segregated, while the segregation of others is random.  “It looks like germline stem cells are segregating very specific strands with quite high bias only for some of  the chromosomes, but not others, so that at least suggests that cells have the machinery to distinguish one chromosome strand over the other and then segregate one into the stem cell in a biased way.”

This finding that the majority of the chromosomes are randomly segregated still leaves the question of why cells need to selectively segregate their centrosomes?  “Ultimately the question everybody is asking is: does the mother or daughter centrosome carry some information, not just microtubules?”

Yukiko doesn’t yet have the answer but can speculate about the possibilities.  “The centrosome itself [could be] associated with some sort of fate determinants. That is not unprecedented. Some fate determining mRNA is associated with just one centrosome during mollusk early embryogenesis.  [Another possibility is that] the centrosomes are used to distinguish two different sister chromatids, to segregate one strand over the other.  Why you have to distinguish one strand over the other strand of the chromosome? I don’t think its for the sake of an immortal strand, I don’t think its because of the DNA mutations or avoiding them, instead I think it’s some epigenetic information that they want to carry. It might be histone modifications or DNA methylation but we don’t have any evidence for that yet.”

Checks and Balances

In addition to their work on centrosome segregation Yukiko’s group is pursuing two other lines of research.  One is examining a novel cell cycle checkpoint, which ensures the correct orientation of centrosomes prior to cell division. “We published one paper suggesting the presence of a new checkpoint that, in GSCs, makes sure the centrosomes are correctly oriented before they get into mitosis. If the centrosomes are not oriented correctly, this checkpoint gets activated and then stalls the cell cycle before entering mitosis. We really want to identify the mechanism of how stem cells are sensing the correct orientation of the centrosome before getting into mitosis.”

The idea of a cell-cycle checkpoint is more at home with cell biologists and Yukiko thinks that it will take some time to convince developmental biologists that what they are describing is a real phenomenon. “I think its going to be a long way to really prove that this really exists, exactly how cells are sensing it, and what is the molecular mechanism, etc. It will probably take multiple papers and probably quite long time; at least five years if not 10 years.”

Yukiko also wants to understand how different stem cell populations interact in tissues and communicate to coordinate their replication and life cycles.  This is a new line of research for the lab and Yukiko wants to explore this direction in the coming years.

“[The Drosophila male gonadal] stem cell niche contains yet another type of stem cell called cyst stem cell. The germline stem cells and cyst stem cells have to coordinate their divisions somehow, we don’t know exactly how yet. Many tissues are made of cell types that are coming from different stem cell lineages. That means the decision of one single stem cell population cannot be enough to maintain the whole tissue. One stem cell population has to coordinate with another stem cell population to make sure that tissues are maintained as a whole. I’m very, very interested in how the stem cells are coordinating with each other.”

Follow Your Passion

What does getting the MacArthur fellowship mean for the future directions in the lab? Most importantly in means freedom to pursue any interesting outcomes that arise in research without the constraints of sticking to a proposed research plan.  “The whole idea of being a scientist is that you can’t really predict anything. If you’re working on something and the answer is so predictable, its quite boring.  Now I feel I do have the freedom to wander off a little bit from the original plan, because of course I didn’t propose anything for the MacArthur!”

Having a passion for science it vital for success as a scientist, but it doesn’t mean that your whole life has to be about work. Yukiko admits that she used to get worried when life’s distractions took too much time away from the bench.  What helped her to establish a career as an independent researcher and develop a life-work balance was learning “laid-back confidence” from her postdoc mentor Margaret Fuller.  “She’s a really good scientist but she is not obsessed by success. You can love science, but it doesn’t have to be your whole life. Other things enter your life that may take time away from the science, but don’t worry.  It might take you a little longer, but you will get to the point where you want to go if you just continue what you’re doing. That is something I learned from her.”

Yukiko spends her free time with her family and taking care of her six-year old daughter. I asked Yukiko if there is something people would be surprised to learn about her. “I am really obsessed with fossil hunting,” she said.  In Michigan, which used to be under tropical water millions of years ago, finding fossilized coral can be as easy as examining the pebbles on the road for a few minutes.  “It’s becoming a fun hobby for my daughter and me.”  After some thought she added: “And another thing my husband always teases me about ‘Where is this assistant professor who sleeps 8-9 hours a day?’ It’s how much I sleep every day!”

For more information:

Profile of Yukiko Yamashita on the MacArthur Foundation website

Press release from the MacArthur Foundation announcing this year’s fellows

Yukiko Yamashita’s lab webpage

References

Yadlapalli Swathi, ChengJun, YamashitaYukiko M. (2011). Drosophila male germline stem cells do not asymmetrically segregate chromosome strands. Journal of Cell Science, 124, 933-9.

Yamashita Yukiko M. (2010). A tale of mother and daughter. Molecular biology of the cell, 21, 7-8.

Yamashita Yukiko M. (2009). The centrosome and asymmetric cell division. Prion, 3, 84-8.

(4 votes)

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There are so many factors for a stem cell to consider when deciding cell fates.  A recent paper from Development discusses how the age of a stem cell can affect its future.

Neurons and glial cells are two major cell types in the nervous system, and both come from the many divisions of neural stem cells (NSCs).  The amazing plastic characteristics of NSCs drive a lot of excitement over their future use in regenerative medicine, but the complex gene network in vertebrates makes understanding NSC plasticity difficult.  Flici and colleagues recently published a paper on NSC cell fate decision-making in the simple CNS of fruit flies.  The transcription factor Gcm was already known to drive glial fate in NSCs.  Flici and colleagues found that overexpression of Gcm in NSCs forced a complete conversion to glial cells.  In addition, NSCs plasticity is affected by age—as NSCs get older, their ability to drive glial cell fates decreases.  After NCSs fell into a quiescent state at old age, Gcm overexpression was no longer able to force glial cell conversion, suggesting that temporal cues, not mitotic potential, drive NSC plasticity.  Finally, Flici and colleagues found that the Gcm-glial cell fate pathway leads to low levels of H3K9ac, which is similar to the low levels of histone acetylation seen in vertebrate glial cells.  In the images above, fly embryos are labeled to show neurons (green) and glial cells (purple).  Control embryos (left) have few glial cells, while embryos with Gcm overexpression (right) have many glial cells.  The longer the Gcm overexpression, the more glial cells develop at the expense of neurons (top is early, bottom is late).  Arrowheads show cells with markers for both glial cells and neurons, an intermediate stage in the conversion towards glial fate.

For a more general description of this image, see my imaging blog within EuroStemCell, the European stem cell portal.

Flici, H., Erkosar, B., Komonyi, O., Karatas, O., Laneve, P., & Giangrande, A. (2011). Gcm/Glide-dependent conversion into glia depends on neural stem cell age, but not on division, triggering a chromatin signature that is conserved in vertebrate glia Development, 138 (19), 4167-4178 DOI: 10.1242/dev.070391

(2 votes)

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Here are the highlights from the current issue of Development:

New blood: vasculature restrains pancreas growth

Although the primary function of blood vessels is to provide organs with the oxygen and nutrients that are essential for tissue growth and maintenance, blood vessels also provide positive paracrine signals during early pancreas development. Now, Yuval Dor and colleagues report that, surprisingly, non-nutritional signals from blood vessels restrain pancreas growth later in development (see p. 4743). In gain-of-function experiments, they show that VEGF-induced hypervascularisation restrains pancreatic growth in embryonic mice. Conversely, the elimination of endothelial cells increases the size of embryonic pancreatic buds. Blood vessels, they report, restrict the formation of pancreatic tip cells, reduce pancreatic lateral branching and prevent differentiation of the pancreatic epithelium into endocrine and exocrine cells both in vivo and ex vivo. The researchers propose, therefore, that the vasculature controls pancreas morphogenesis and growth by reducing branching and by maintaining the undifferentiated state of primitive epithelial cells. These unexpected findings might have important implications for the derivation of insulin-producing β-cells from embryonic stem cells for the treatment of diabetes.

Hesr1 and Hesr3 regulate satellite cell fate

During postnatal growth, satellite cells (skeletal muscle stem cells) divide to provide new myonuclei for growing muscle fibres, but in adult muscle they are maintained in an undifferentiated quiescent state except during muscle regeneration. Notch signalling regulates stem cells in many tissues, including skeletal muscle, and here, So-ichiro Fukada and co-workers investigate whether the Notch target genes Hesr1 and Hesr3 are involved in the generation of satellite cells (p. 4609). They report that Hesr1 and Hesr3 are expressed simultaneously in neonatal and adult mouse satellite cells and show that, although Hesr1 and Hesr3 single-knockout mice have no obvious satellite cell or muscle regeneration abnormalities, the postnatal generation of undifferentiated quiescent satellite cells is impaired in Hesr1/3 double-knockout mice. Moreover, satellite cell numbers gradually decrease in Hesr1/3 double-knockout mice because of premature differentiation, and the mice develop an age-dependent muscle regeneration defect. Thus, the researchers conclude, Hesr1 and Hesr3 play crucial roles in skeletal muscle homeostasis by regulating the undifferentiated quiescent state of satellite cells.

Endothelial cell movements during angiogenesis

During angiogenesis, new blood vessels sprout from an existing vascular network, elongate and bifurcate to form a new branching network. The individual and collective movements of vascular endothelial cells (ECs) during angiogenic morphogenesis are poorly understood but, on p. 4763, Koichi Nishiyama and colleagues provide some new insights into these movements. Using time-lapse imaging and a computer-assisted analysis system to quantitatively characterise EC behaviours during sprouting angiogenesis, they show that ECs move backwards and forwards at different velocities and change their positions relative to each other, even at the tips of elongating branches in vitro. This ‘cell mixing’, which also occurs in vivo at the tips of developing mouse retinal vessels, is counter-regulated by EC-EC interplay via Dll4-Notch signalling and might be promoted via EC-mural cell interplay. Finally, the researchers show, the dynamic behaviour and migration of ECs contribute to effective branch elongation. Thus, cell behaviours during angiogenesis and other forms of branching morphogenesis might be more complex and variable than previously thought.

JAK/Stat signals touch Tinman’s heart

During Drosophila heart development, intercellular signalling pathways activate a conserved cardiac-specific gene regulatory network by inducing the expression of the transcription factor Tinman (Tin) in the dorsal mesoderm. Stat92E, the transcriptional effector of the JAK/Stat signalling pathway, is a direct target of Tin and, on p. 4627, Eric Olson and colleagues characterise JAK/Stat signalling during cardiogenesis for the first time. They show that Drosophila embryos with mutations in the JAK/Stat ligand upd or in Stat92E have non-functional hearts with luminal defects and inappropriate cell aggregations. The JAK/Stat pathway, they report, is active in the dorsal mesoderm when the initially broad mesodermal expression pattern of tin becomes restricted to cardiac and visceral muscle progenitors, which occurs after dorsal mesoderm progenitor specification. Finally, they show that JAK/Stat signals activate Enhancer of Split complex genes to restrict Tin expression, thereby regulating heart precursor diversification. Overall, these findings show that JAK/Stat signalling regulates heart development and identify an autoregulatory circuit by which tin restricts its own expression domain.

Careless tALK predisposes to neuroblastoma

Neuroblastoma, the most common extracranial solid tumour in childhood, arises from cells of the developing sympathoadrenergic lineage. Activating mutations in the gene encoding the tyrosine kinase receptor anaplastic lymphoma kinase (ALK) have been identified in both familial and sporadic cases of neuroblastoma so might Alk signalling control proliferation in this lineage? On p. 4699, Hermann Rohrer and colleagues report that forced expression of wild-type ALK or neuroblastoma-related constitutively active mutant ALK increases the proliferation of cultured immature chick sympathetic neurons and their expression of the proto-oncogene NMyc and of the neurotrophin receptor trkB. By contrast, Alk knockdown both in vitro and in vivo reduces sympathetic neuron proliferation. Furthermore, the Alk ligand Midkine (Mk) is expressed in immature sympathetic neurons, they report, and in vivo knockdown of Mk also reduces sympathetic neuron proliferation. Together, these results indicate that Mk/Alk signalling controls the extent and timing of sympathetic neurogenesis. Thus, the predisposition to neuroblastoma that is associated with activating ALK mutations might be the result of aberrant neurogenesis.

(Bell)ringing the changes in plant phyllotaxis

Complex networks of regulatory genes control morphogenesis but how are these networks translated into the local changes in tissue growth that shape multicellular organisms? Jérôme Pelloux and co-workers (p. 4733) have been investigating the modulation of phyllotaxis (the arrangement of leaves and flowers along plant stems) in Arabidopsis by the transcription factor BELLRINGER (BLR). In plants, the formation of new lateral organs depends on demethylesterification of homogalacturonan (HG), a major component of plant cell wall pectins. The researchers show that ectopic primordia form in the floral meristem of Arabidopsis blr mutants because of ectopic expression of the pectin methylesterase PME5, which changes the demethylesterification state of HG. Thus, BLR normally represses PME5 expression in the meristem, thereby influencing the establishment of the phyllotactic pattern. However, in the elongating stem, the researchers report, BLR activates PME5 expression to maintain phyllotaxis. These results identify BLR as an important component of the regulatory network that controls HG demethylesterification and, in turn, phyllotaxis in Arabidopsis.

Plus…

Coordinating cell behaviour during blood vessel formation

Geudens and Gerhardt review recent progress in our understanding of blood vessel formation, which has been driven by advanced imaging techniques and a combination of powerful in vitro, in vivo and in silico model systems.

See the Review article on p. 4569

An interview with Gordon Keller

Gordon Keller is Director of the McEwen Centre for Regenerative Medicine at the University Health Network in Toronto, Canada. His research applies concepts from developmental biology to the investigation of the lineage-specific differentiation of mouse and human embryonic stem (ES) cells. He became an Editor of Development in 2011, and recently we asked him a few questions to find out more about him and his research.

See the Spotlight article on p. 4567

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The final day of the meeting continued with vivid discussion and scientific exchange during the presentation sessions as well as during the breaks. Coming back to the initial focus of the meeting, today’s remaining topics centered on the fly as a model system to study fundamental regulators of cell proliferation.

Nic Tapon, at the London Research Institute, presented a synopsis of the Hippo signaling pathway and novel insights into its regulation. This inhibitory cascade of kinases is involved in proliferation control and is conserved in mammals including humans where it has been implicated in cancer and stem cell biology. In the absence of inhibitory Hippo signaling, Yorkie, a downstream co-activator of Tef/Tead transcription factors, translocates to the nucleus and promotes proliferation and can ultimately lead to tumor growth. However, the upstream regulation of the Hippo pathway is still unclear, although a number of links to epithelial polarity pathways have been demonstrated. Nic Tapon’s talk focused on unraveling the regulatory inputs upstream of Hippo using cell based RNAi screens. Subsequent discussion included references to the previous day’s discussion of apico-basal polarity proteins involved in murine retinoblastoma (Rod Bremner’s talk) and in growth control in the fly (Helena Richardson’s talk).

Related to this, and with similar immediate relevance for human cancer, Ginés Morata presented conceptual and experimental advance on the role of tissue-level signaling and proliferation control. Referring to a classic, yet continuously relevant, experiment conducted during his own graduate studies (Morata & Ripoll, 1975), he introduced the concept of cell competition as a means of growth inhibition. He showed in contrast to lethal giant larva (lgl) mutant clones, which are outcompeted and eliminated by apoptosis, lgl ras double mutant clones overgrow and form tumors with an efficiency which increases the more clones are induced. Even though lgl ras clones overgrow, cells at the clone edges of undergo apoptosis, which altogether suggests that there is a minimum number of highly proliferating mutant cells (a microenvironment) that need to be present in order to evade elimination by cell competition. In addition he presented data suggesting that the apoptotic cells themselves could promote the proliferation of neighboring cells by secreting growth-promoting factors.

Concluding the scientific program of the meeting, the academic organizers Anna Philpott (Cambridge) and Nancy Papalopulu (Manchester) summarized the main aspects and recurring themes of the meeting as well as the remaining challenges in the field.

While the meeting had been somewhat “neurocentric” the identified common concepts and mechanisms are applicable to other tissue and cellular contexts. Indeed, “neurocentricity” may be a result of the fact that these concepts and mechanisms have been best elucidated in the nervous system to date. One important notion was interaction between cell cycle regulators and components various signaling pathways. Moreover, an increasing emphasis is placed on understanding the temporal and spatial dynamics of cell cycle and differentiation mechanisms. Another interwoven thread was the significance of identifying similar or related mechanisms in a range of organisms, not only in the mouse, but in frog, fly and in mammalian stem cell systems.

The utility of meeting platforms such as this one were praised, referring to newly identified areas of joint interest between the attendants, and resulting in facilitation of collaborations and future research. Specific for this meeting format was the truly generous opportunity for interaction and scientific exchange. Practically equal time was allotted to the discussion as to the actual talk within the sessions. Moreover, extended coffee breaks and joint activities enabled the lively discourse of the participants coming from all around the world. It was acknowledged that the attending junior investigators and discussants brought a certain freshness and creativity to the table, beyond fostering their career development through immediate interactions and informal discussion with leaders in the field. In summary, the meeting very well matched the format of the company of biologists workshops. While it already fulfilled its aim of promoting the understanding of “growth, division and differentiation” during development, more benefit and spin-offs are likely to arise from the continued exchange between its attendants.

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This is the first post of others to come on the first course on insect neuroscience and Drosophila neurogenetics in Uganda, that is being partially funded by The Company of Biologist. The motivation for organizing the course is that currently in East Africa, and most parts of Africa, research in experimental neuroscience is carried out mostly with rats, which are expensive. However, almost no one is using Drosophila, an inexpensive model organism that in Europe and the U.S is leading in neuroscience and basic medical research. The course will include theoretical and practical (laboratory) sessions. It is intended for graduate students and Junior Faculty who are interested or involved in teaching or doing research in neuroscience at universities in Africa. This year course will start next week, and thanks to the support from The Company of Biologist, we will be welcoming students from Uganda, Tanzania, Kenya, Malawi, Nigeria, and Cameroon. The people involved in the project include a local organizing committee that is taking care of all the organization in Ishaka (where the medical campus of the Kampala International University is based, place where the course will take place), and faculty: Dr. Baden,  Dr. Palacios, Dr. Martin-Bermudo, Dr. Vicente, and myself (Dr. Prieto Godino). I will post here some other general posts about the course, but if you are interested and you would like to know more about it, and how it is running everyday you can follow our Facebook or our blog pages.

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