You just started your research career, or maybe you just moved fields. The first thing on your to-do list is to catch up with the literature. What has been the latest progress? What are the open questions in the field? Ideally, you would go all the way back to the beginnings of the field and acquire a broad perspective of how research has changed and how the earlier works have impacted on current research. But time is short. The literature is just too vast, and the bench is calling, urging you to get started on your experiments. So you read a couple of recent comprehensive reviews, a bunch of papers from the last few years and a handful of the most significant earlier studies and move on to start your research project.

There is nothing wrong with this approach- there really is a vast number of papers out there, and time is limited. Unfortunately, this means that many important papers are overlooked. Certain ‘facts’ are taken for granted, and how they were obtained is not questioned. That chance encounter with an old result that could change the course of your research never takes place.

Aware of these issues, we have decided to launch a new series of posts called ‘Forgotten Classics of Developmental Biology’. We asked prominent researchers from all areas of developmental biology to suggest their favourite hidden gems and to explain why we should all revisit them. In this series we will provide you with a summary of each paper, alongside comments from the person who recommended it as well as from other researchers in the field. For those papers still not freely available online, we also aim to ask the publishers if they will provide free access to each paper for a limited period of time after the post is published. We hope this will give everyone a chance to benefit from re-reading these forgotten classics!

The list of papers that we plan to feature in this series is still growing, so if there is a ‘Forgotten Classic’ that you think we should cover, please get in touch. We would love to hear your suggestions.

(11 votes)

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This cartoon was first published in the Journal of Cell Science. Read other articles and cartoons of Mole & Friends here.

Part I- ‘The imposter’

Part II- ‘The teaching monster’

Part III- ‘The Pact’

Part IV- ‘The fit’

Part V- ‘The plan’

Part VI- ‘FCTWAWKI’

Part VII- ‘Beaten and bruised’

(2 votes)

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The signalling systems that conduct the orchestra of embryonic development are fantastically complex and dynamic. We owe much of our knowledge of in vivo signalling dynamics to advances in microscopy and protein tagging with fluorescent reporters that have allowed visualization of signalling proteins. Looking forward, however, it is clear that simply analyzing the localization patterns of proteins is only the first step to fully understand signalling processes. Of course, a protein’s presence at a particular time or place in the embryo does not tell us if it is actively signalling or lying dormant until its activity is required. Therefore, generic methods to distinguish actively signalling proteins from passive proteins will be tremendously useful advances for researchers interested in developmental processes.

A few years ago, Darren Gilmour at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, realized that since many signalling events lead to the degradation, stabilization, or relocalization of participating proteins, methods for detecting changes in protein turnover could provide powerful proxies for in vivo signalling activity. Gilmour and his graduate student Erika Donà therefore took advantage of a dual-color genetically encoded fluorescent reporter called a “tandem timer”, newly developed by Michael Knop in the next-door lab at the EMBL. Tandem timers report on the age of protein populations through the relative fluorescence of adjacent slow- and fast-maturing fluorophores (Khmelinskii et al. Nat. Biotechnol 2012). In collaboration with Knop and his postdoc Anton Khmelinskii, Gilmour and Donà tagged the chemokine receptor Cxcr4b with a tandem timer with a view to observing Cxcl12a chemokine signalling activity across a migrating tissue, the zebrafish posterior lateral line primordium. They wagered that this strategy was likely to inform on chemokine signalling activity since Cxcr4b receptors undergo rapid internalization and degradation upon ligand-mediated activation. Higher Cxcl12a levels would increase Cxcr4b internalization rate and this should be reflected by a decrease in the receptor’s population age (increased protein turnover). Gilmour and Donà also understood the potential long-term implications of their attempt; a successful proof-of-principle study might lead to the adoption of the tandem timer as a generic tool for the detection of signalling activities.

At the time I was a postdoctoral researcher in Wolfgang Huber’s group at EMBL, and having collaborated with Knop and Khmelinskii on the original tandem timer paper, I was happy to get involved in this first project using tandem timers in embryos. Using image processing and analysis tools from R and Bioconductor software, I measured tandem timer signalling readouts from 3D images of migrating tissues, and used a mathematical model of timer behaviour to interpret the results. The model describes the maturation kinetics of the two fluorophores on the timer, as well as production and degradation rates of the tagged protein. What surprised and delighted me throughout my collaboration with Gilmour and Donà, was the extent to which quantitative analysis and modelling was able to feed back on subsequent experimental design, and positively influence later results. Ultimately our tandem timer observations, along with other data, allowed us to demonstrate that a self-generated chemokine gradient guides the migration of the zebrafish posterior lateral line primordium (Donà et al. Nature 2013).

Tandem timers can be constructed with virtually any combination of spectrally separated fluorescent proteins with different maturation rates. Therefore, the first question an experimentalist typically asks when using tandem timers is: which fluorophores should I choose? We have been contacted by many groups asking exactly this question. As our ability to design timers and interpret timer data has benefited greatly from the use of modelling, we decided to write a paper outlining how our modelling tools could be used by other researchers interested in tandem timer research. To make these tools easily accessible we developed an interactive web application, TimerQuant, and made all our code available through the open-source software platform Bioconductor. For our new paper, which is now published in the journal Development (Barry et al. Development 2016), we systematically investigated the effect of relevant experimental parameters on timer signal, a measure of how good a particular timer is at detecting differences between two protein half-lives. To validate the predictions of our model, we reinvestigated the Cxcr4b signalling gradient identified in our original study using three tandem timers that had the same fast-maturing fluorophore (sfGFP), but different slow-maturing fluorophores (mKate2, mCherry, TagRFP). We found that timer signal decreased as the maturation times of the slow- and fast-maturing fluorphores became more similar. Readouts became noisier as protein abundance decreased. Timer signal increased with the maturation time of the slow-maturing flurophore, albeit at the expense of noisier readouts. While these conclusions might already be expected from a more qualitative reasoning, the quantitative model also led to some unexpected and intriguing findings. For example, Förster resonance energy transfer (FRET) between the fast- and slow-maturing fluorophores actually increased timer signal, a prediction that was borne out in our experiments, and which may be an important consideration for future timer designs.

In the initial model protein production (expression) and degradation rates were kept constant. Given that in developmental contexts these are likely to change over time, we decided to explore the effect of dynamics on timer ratio profiles. We modelled constant increases and decreases of protein expression and degradation rates as well as sudden bursts of expression and degradation, and looked at model solutions over time. The simulation results showed timer ratio profiles over time producing clear, characteristic responses to expression and degradation dynamics. We were surprised by the extent to which expression and degradation responses were distinguishable from one another. These additions to the model further help in the interpretation of timer ratio results in non-steady state conditions, which is often the situation when studying dynamic developmental processes. Moreover, as degradation rate could be experimentally fixed, for example by using non-degradable (or slowly degradable) versions of tandem timers, these model predictions open up the exciting possibility of using tandem timers to observe gene expression dynamics with time-lapse microscopy.

Explore Further:
Interactive TimerQuant software applications including those showing timer responses to dynamically changing gene expression can be used online at http://chronos.embl.de/TimerQuant/ or offline through the TimerQuant software package on the Bioconductor website.

Papers Referenced:
1. Barry JD, Donà E, Gilmour D and Huber W, TimerQuant: A modelling approach to tandem fluorescent timer design and data interpretation for measuring protein turnover in embryos, Development 143(1), 2016
2. Donà E, Barry JD, Valentin G, Quirin C, Khmelinskii A, Kunze A, Durdu S, Newton LR, Fernandez-Minan A, Huber W, Knop M and Gilmour D, Directional tissue migration through a self-generated chemokine gradient, Nature 503(7475), 2013
3. Khmelinskii A, Keller PJ, Bartosik A, Meurer M, Barry JD, Mardin BR, Kaufmann A, Trautmann S, Wachsmuth M, Pereira G, Huber W, Schiebel E and Knop M, Tandem fluorescent protein timers for in vivo analysis of protein dynamics, Nature Biotechnology 30(7), 2012

(4 votes)

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Here on the Node you can sign up for several mailing lists, but since they were implemented at different stages each sign up page was in a different place. To makes things simpler and easier, we have now created a single page where you can sign up to our three mailing lists:

• Node Weekly emails– a list of all new posts published on the Node in the last week.
• Occasional writing ideas– for those who want to post on the Node but need some inspiration.
• Occasional news from The Company of Biologists– updates from our sister journals, workshops and grants.

If you haven’t sign up to these lists yet, or only signed up to some, you can do it now in our new Sign up page. We also added a new Sign up box on the right hand side column of the Node, so that this new page is easy to find. New users will also be given the option to sign up to these email lists upon registration.

You will also notice that that our daily update emails have now become weekly. In our recent survey several of you commented that our update emails were sent too frequently, so we hope that a weekly email will work better. Our first weekly email will arrive to your inbox tomorrow, also featuring a new look. As always, we welcome your feedback on these changes. Please feel free to leave a comment here or drop us an email!

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The BSDB Newletter 2015 is out! As you might have noticed, there was no BSDB summer newsletter this year. The reason for this is that the BSDB committee has taken the sensible decision to reduce them to one edition a year. Newsletters clearly do no longer play the same role as they used to. In times of the internet, they are no longer needed to update members on new developments of society matters or in the area of Developmental Biology. This is now done far better through the BSDB website and through The Node (also see page 9 of the Newletter). However, we feel that providing an overview of the year still is a service we owe to BSDB members, and which might provide an informative document also for future generations.

I hope you enjoy this issue and, in the name of the BSDB committee, would like to wish you a happy and successful new year 2016.

Andreas Prokop (Communications officer)

P.S. If you are interested in BSDB newletters of the last 10 years, they are archived on our website.

(3 votes)

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A running joke amongst avian developmental biologists is that the chicken (Gallus gallus) is the tastiest of the model organisms. A typical response from some of my mouse, frog or fish friends, would be that that is where the advantages end – the lack of the ability to do genetics in birds present limitations in the types of molecular analyses that could be done. Despite being so tasty, the chick is not the most cost effective lab animal to keep: It is big, and requires a large amount of space for housing, and it has a slow generation time of almost a year. These points make the development of genetic techniques in chick prohibitive to most labs. About 5 years ago, we decided to see what could be done with the zebra finch. Zebra finches have been widely used in studying behaviour and neural circuitry. They have the advantage of being small and have a generation time of about 3-4 months, the same as that for mouse. With support from the RIKEN CDB Director’s fund (Masatoshi Takeichi at that time) and from the Animal Facility (particularly Shinichi Aizawa, its then head), establishing our finch colony in the RIKEN CDB was straightforward. We bought the founders from pet shops in the Kansai region of Japan and housed them in our newly appointed finch room at the CDB. At this point we realised that many of the published protocols for finch husbandry were not optimal for egg production and so we decided to invest time optimizing these protocols.

Siu-Shan Mak (Suzanne) the lead post-doc who really drove the study, and Anna Wrabel-Suzuki, the animal technician in charge of looking after the birds, spent the first year studying the behaviour of the birds, and checking the quality of the eggs, tweaking the diet, lighting, and cage conditions so that we could house them in the best conditions for optimal fertile egg production. It was during these checks of egg quality that Suzanne noticed that the finch embryo was at a younger stage than the chick at laying. A small note here; birds undergo some development in utero, before the egg is laid. Chicks and quails lay their eggs when the embryos are just about to gastrulate (Eyal-Giladi and Kochav 1976). We found that finches lay fairly early, with the embryo at a late blastula stage. We thought that this difference would allow us some additional insights into early avian development.

Around this time, the groups of Jennifer Nichols and Austin Smith published a series of papers describing the stage in mouse at which embryonic stem cells (ES cells) that showed naïve pluripotency could be derived (Boroviak et al. 2014). In this state, naïve ES cells can give rise to all cell types found in the embryo. It contrasts with primed pluripotency, where the cells (also called epiblast-derived stem cells or EpiSCs) have a more restricted potential (Nichols and Smith 2009). Another key difference of these cells is their sensitivity to the inhibition of an important signalling pathway intermediate MAP kinase: naïve ES cells were resistant to its inhibition whereas EpiSCs were not (Nichols and Smith 2012). The group showed that mice blastocysts at around E4 were able to generate naïve ES cells. At this stage the epiblast has been specified (as shown by molecular markers) but is yet to epithelialise. We found that the finch blastoderm at laying is similar: The epiblast, and indeed the hypoblast, are both specified but there is little morphological segregation, reminiscent of the pre-epithelialised epiblast. When we took cells from newly laid finch embryos, and cultured in the presence of a MAP kinase inhibitor, they retained the expression of pluripotent markers, and markers of naïve ES cells. Cells taken from later staged finches or from newly laid chicken embryos did not express pluripotent markers when MAP kinase was inhibited, behaving more like primed pluripotent cells. These results were presented in our recent paper in eLife (Mak et al. 2015).

We think that at the very least, the finch embryo could provide some comparative insights into the restriction of pluripotency in amniotes, and possibly would enable the generation of testable hypotheses when thinking about the evolution of pluripotency in mammals. Our hope that by combining new genome engineering tools with long-term finch ES cell cultivation and subsequent chimera generation, this work sets the stage for a tractable, genetic avian model system. These are some of the ideas we will be thinking about in our new labs in Kumamoto (Guojun) and in Bangalore (Raj).

Boroviak T, Loos R, Bertone P, Smith A, Nichols J. 2014. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol 16: 516-528.

Eyal-Giladi H, Kochav S. 1976. From cleavage to primitive streak formation: a complementary normal table and a new look at the first stages of the development of the chick. I. General morphology. Dev Biol 49: 321-337.

Mak S-S, Alev C, Nagai H, Wrabel A, Matsuoka Y, Honda A, Sheng G, Ladher RK. 2015. Characterization of the finch embryo supports evolutionary conservation of the naive stage of development in amniotes. Elife. doi:10.7554/eLife.07178

Nichols J, Smith A. 2009. Naive and primed pluripotent states. Cell stem cell 4: 487-492.

Nichols J, Smith A. 2012. Pluripotency in the embryo and in culture. Cold Spring Harbor perspectives in biology 4: a008128.

(10 votes)

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BMP Signalling in Cancer

15—17 March 2016

St. Catharine’s College, Cambridge, UK

Join the Biochemical Society in exploring the mechanisms of BMP signal transduction and regulation of signalling, and discussing how genetic and epigenetic alterations result in aberrant signalling and how this leads to cancer. The BMP signalling pathway is a key therapeutic target and we will consider how to manipulate the pathway with small molecules or biologics. The BMP Signalling in Cancer conference will bring together researchers from academe and industry, and will be a great opportunity for those working on BMP signalling, cancer, stem cells, structural biology and drug discovery to share data and interact in a vibrant, but informal environment.

Topics

• Mechanisms of BMP signalling
• Deregulation of BMP signalling in cancer and therapeutic approaches
• Genetic and epigenetic alterations in BMP pathway components
• BMP signalling in disease

There are selected oral communication slots in the programme and flash poster presentation opportunities available from poster abstracts.

Submit your abstract by 12 January to present your work.

(No Ratings Yet)

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This four-day long time-lapse shows the development of pre-implantation mouse embryos from the 2-cell stage to over 100-cells as the expanded blastocysts hatch from their zona pellucidas. These embryos were imaged using two-photon microscopy, which enabled us to visualize and track individual cells and lineages throughout pre-implantation development with good spatiotemporal resolution and excellent viability. Bright-field images were collected simultaneously, allowing us to visualize the over-all morphology of the embryos as they developed. Such a complete, bright-field movie of developing pre-implantation embryos is extremely useful for demonstrating the rapid and dynamic growth that occurs during the early stages of mammalian development.

Since our initial work on the subject had just been published when I made this movie, few people ended up seeing it outside of conferences or talks. Frequently, however, people would ask me to use it in their own slides and lectures, and we wanted to make it available to the community at large. The Node has been an excellent resource for developmental biologists, and I hope people are able to find this movie as useful and informative as the many others shared on The Node.

(Time stamp: hh:mm:ss, scale bar 40 microns. Source: McDole, K. and Zheng, Y., Carnegie Institute for Science – Department of Embryology).

(15 votes)

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This editorial by Olivier Pourquié and Katherine Brown first appeared in Development.

As a journal with its community very much at its heart, we here at Development believe it is essential to ensure we take your opinions into account when planning for the future. It was with this ethos in mind that we recently carried out a community survey looking at how well the journal reflects the current state and future directions of the field. Firstly, we’d like to take this opportunity to thank all of you who took the time to complete the survey – we were overwhelmed by the number of responses and by the detailed feedback we received. We’d like to report back on the results of that survey and on how these are now influencing the journal’s plans.

Developmental biology as a field is evolving. While these aren’t necessarily easy times for fundamental research, with funding tight and an ever-increasing pressure for work to have ‘translational impact’, we would argue that they are exciting times for our field. Genome sequencing and editing technologies have opened up a world of non-traditional model systems to genetic analysis, allowing us to probe the evolutionary and developmental mechanisms underlying the development of a wide range of species. Quantitative and computational techniques allow us to probe these mechanisms in greater detail. In vitro technologies using stem cells provide tools to analyse fundamental principles and mechanisms of cell proliferation, differentiation and even morphogenesis. These techniques are proving to be particularly important for providing insights into human development, which can not be addressed in vivo. Development’s mission is to publish the best research across the scope of our field: to publish papers at the cutting edge of modern developmental biology, as well as continuing to be the natural home for the best work in more traditional areas.

So, how well are we succeeding in that goal, and how well do you – our community – think we are doing? These were some of the questions we set out to explore with our recent survey, which gathered over 700 responses and included lots of detailed comments (see Box 1 for some of the key statistics). We’re still sifting through some of the data, but this has given us a very valuable impression of where you think Development sits within the publishing landscape. In general, you told us that the journal reflects our field very well. While a few of you raised some concern about a perceived decline in quality or influence, others told us that Development is the premier journal for the field and a key source of essential reading matter. We asked whether particular fields were over- or under-represented in the journal. Most of you think we are doing a good job in covering a broad spectrum of areas, although your comments have highlighted particular areas (such as quantitative, computational and systems biology, ‘omics, evo-devo and plant development) where perhaps we need to do more to attract more high-quality submissions. We are looking at ways of doing this and are, for example, in the process of putting together a Special Issue on Plant Development, which is still open for submissions (see http://dev.biologists.org/content/special-issue-plant-development). Some of you feel that we are publishing too much stem cell work (more on which below) or that too many of our papers use too narrow a range of model systems. But in general, it seems that although there are always improvements to be made, you feel that the papers we publish reflect the diversity of research being carried out in our community.

————————————————————————————————————————————————————

Box 1. Key survey responses

Question: Considering the content of Development over the past year or so, how well do you feel the journal reflects the state of the modern developmental biology field?

Rate on a scale of 1 (not at all well) to 5 (very well)

Average score: 4.15

Question: Please rate the extent to which you think changing Development’s name (e.g. to Development and Stem Cells or similar) could benefit/disadvantage the journal.

Strong/slight disadvantage: 65%; Neutral: 21%; Strong/slight advantage: 14%

Question: Please rate the extent to which you agree/disagree with the following statements (only selected statements shown):

‘I am supportive of Development’s move into the stem cell field and I think the balance of content is about right.’

Agree: 48%; Neutral: 27%; Disagree 25%

‘I believe there is space for some stem cell papers in the journal, but only where there is a direct link to an in vivo developmental process.’

Agree: 72%; Neutral: 15%; Disagree 13%

‘I feel that stem cell papers do not belong in a developmental biology journal.’

Agree: 11%; Neutral: 17%; Disagree 72%

————————————————————————————————————————————————————

The second part of the survey focussed on our recent expansion into the stem cell field. This has been one of our major strategies over the past few years, and one that we have discussed extensively in previous editorials (e.g. Pourquié et al., 2013). We continue to believe strongly that this is an important direction for the journal (and for the field more generally), but we wanted to gauge opinions in the community and to ensure that we have your support in this. As we expected, responses here were quite polarised. The vast majority of you agree that Development should be publishing stem cell papers – particularly those where there is a clear link to an in vivo developmental biology process – and most of you feel that we have the balance of content about right. Your comments indicate that you, like us, recognise the deep connections between the two fields, and we are heartened to see that we have your support. That said, some of you expressed strong opposition to this move, arguing that most stem cell research isn’t really developmental biology, that stem cells are a ‘hot topic’ right now but that this is a passing fad, or that there are plenty of other stem cell journals out there and that Development should stick to core aspects of developmental biology. While we respect these opinions, our viewpoint is rather different. Clearly there are aspects of stem cell research, particularly the more translational work, that do not directly relate to developmental biology, and these do not belong in the pages of Development. Still, much of stem cell research, even the exclusively in vitro work, is clearly informed by developmental principles, or contributes to our understanding of these principles. The stem cell field is here to stay, although it will – like developmental biology – evolve over time, and we see an important role for Development in bridging the gap between these two interlinked fields.

We will therefore continue to strengthen our efforts to attract the best stem cell research to the journal. In particular, we are very keen to publish more research on human development (a field that several of you told us was under-represented in our pages). Our 2015 Special Issue on Human Development (see Pourquié, 2015) showcased some fantastic research in this field, and we have recently attracted more submissions in this area – a trend we hope we will continue. To this end, we are organising a meeting on this topic (a follow-up to our highly successful 2014 event) for September 2016; for more details, see http://www.biologists.com/meetings/from-stem-cells-to-human-development-2016/. We are also delighted to announce that we have recruited two new editors to Development’s editorial team. Paola Arlotta has joined the team to replace Magdalena Götz, who stepped down last year and whom we thank for her dedicated service to the journal. Paola, who is based at Harvard University (USA), is an expert in cortical neurogenesis, with a strong interest in how neuronal progenitor fate is regulated and how our understanding of these processes might impact on potential regenerative therapies for nervous system disorders. Rong Li steps down from the editorial team at the end of 2015, and we are also very grateful for her contribution over the past five years. Rather than recruit a direct replacement for Rong, we have instead decided to create a new ‘Guest Editor’ position. This temporary position will allow us to focus on a particular field of interest, and will be used over time to promote different up-and-coming areas of developmental biology. In keeping with our strategy to promote the analysis of developmental mechanisms using stem cell systems, our first Guest Editor will be Melissa Little (Murdoch Childrens Research Institute, Australia). Melissa has a long-standing interest in kidney development, and is now pioneering research into generating kidney tissues in vitro from human stem cells. We are absolutely delighted to welcome both Paola and Melissa to the editorial team.

Returning to the survey, perhaps the most controversial part asked whether Development should consider changing its name to reflect the inclusion of stem cell research. This is something we had been discussing internally – as it might help us to attract more and higher quality submissions from the stem cell community, as well as more accurately echo the current content of the journal – but without a clear consensus among the editorial team we wanted to gauge the opinion of the broader community. A clear majority of you said that changing our name would disadvantage the journal. While most of you responded that any potential name change would not affect the likelihood of your submitting to, reviewing for or reading Development, it is clear that our community wants Development to remain ‘Development’. And so it shall.

What other lessons have we learned from this survey? Interestingly, it seems that opinions about the journal are remarkably consistent across the age and career stage range. We already knew that many more established members of our community recognise the value of a journal like Development, but it was particularly pleasing to see that most early career scientists do too. We hope this stands us in good stead for the future, as those students and postdocs progress through their career. We also saw that, while many of you know about our publisher – The Company of Biologists – and its not-for-profit status and charitable activities, a sizeable proportion of the community does not know much about the organisation behind the journal. For those of you interested in finding out more, please see our recent editorial (Pourquié et al., 2015). Finally, and perhaps most importantly, we learned (from the size and nature of the response to this survey) just how much you care about Development. Your continued support and engagement is what keeps Development the important journal that it is, and we are hugely grateful to have it.

We would like to close by thanking all those who contribute to Development’s success. Our editors, editorial board members, staff and authors gain public recognition, but the importance of our dedicated referees should also be acknowledged. All those who reviewed for the journal in the past 12 months are listed in the supplementary information, and we are truly thankful for their time and dedication that ensures the quality of the work we publish.

References

1. Pourquié, O. (2015). Human development: a Special Issue. Development 142, 3071–3072doi:10.1242/dev.129767.
2. Pourquié, O.,Bruneau, B.,Götz, M.,Keller, G. and Smith, A. (2013). Stem cells and regeneration: a Special Issue. Development 140, 2445 doi:10.1242/dev.098350.
3. Pourquié, O.,Brown, K. and Moulton, C. (2015). Developing a new look. Development 142, 3803–3804doi:10.1242/dev.131979.

(2 votes)

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Here are the highlights from the current issue of Development:

Making and shaping the lung epithelium

Gas exchange in the lung occurs across the alveolar epithelium, which consists of flattened AT1 cells that comprise the gas exchange surface and cuboidal surfactant-producing AT2 cells. Both cell types are generated from a bipotential progenitor, but the events surrounding cell differentiation and morphogenesis of the alveolar structure are still poorly understood. On p. 54, Jichao Chen and colleagues investigate the differentiation, morphogenesis and plasticity of mouse AT1 cells in the peri- and postnatal lung. They find that, although alveolar surface area increases dramatically in the weeks after birth, AT1 cells do not appear to proliferate; increase in surface area is achieved by a ∼10-fold increase in cell size. AT1 cell differentiation involves a two-step process of cell flattening and cell folding as alveolar septation occurs. Moreover, signals from the AT1 cells may regulate alveolar angiogenesis and secondary septation. Finally, although AT1 cells are highly morphologically differentiated, they still show some degree of plasticity: overexpression of SOX2, which promotes airway differentiation, in developing or mature AT1 cells causes retraction of the cellular extensions and induces proliferation. Together, these data shed light on the mechanisms underlying postnatal lung development and add to accumulating evidence for an unexpected degree of plasticity in the lung epithelium.

The evo-devo of neural progenitors

Underlying the intricate complexity of the vertebrate brain is a complicated set of developmental programs regulating proliferation and differentiation of the different regions and neuronal types. In the mammalian neocortex, two major types of progenitor cells have been characterised: apical progenitors (APs) that divide at the apical surface of the ventricular zone and basal progenitors (BPs) that divide in the subventricular zone. BPs can be further subdivided into different types, including intermediate progenitors expressing the Tbr2 marker and cells with stem cell-like properties: basal radial glial cells (bRGs). To date, bRGs have only been characterised in mammals, but the evolutionary origin of different BP populations is uncertain. Now, Tadashi Nomura and co-workers (p. 66) characterise a bRG-like population in the chicken pallium (a region of which is homologous to the mammalian neocortex). These cells share many properties with mammalian bRGs, including their morphology, position, orientation of mitoses and response to various genetic manipulations. The authors further show that this lineage is distinct from Tbr2⁺ progenitors, which in the chick – unlike in the mouse – appear to be non-proliferative. Furthermore, surveying a range of amniotes and amphibians suggests that BPs are quite widely distributed in vertebrates, suggesting they may be a more ancient evolutionary innovation than previously thought.

A balancing act at the synapse

Matrix metalloproteinases (Mmps) and their inhibitors (Timps) are thought to be important for synaptogenesis, but their roles are poorly understood – at least in part because there is significant complexity and redundancy in the mammalian matrix metalloproteome. Kendal Broadie and colleagues (p. 75) have therefore turned to Drosophila, which have just two Mmps and a single Timp, as a simpler system to assess the roles of Mmps and Timps at the developing neuromuscular junction (NMJ). They find that depletion of either mmp1 or mmp2 alone leads to increased synaptic architectural complexity as well as elevated functional neurotransmission. Surprisingly, however, simultaneous loss of both Mmps or overexpression of Timp, has a much weaker phenotype. It appears to be the balance of Mmp1 and Mmp2 on both pre- and postsynaptic sides of the NMJ that is critical for appropriate synapse formation. The authors find no ultrastructural defects, but rather that dysregulation of Mmp activity impacts synaptic Wnt signalling, with the level and localisation of the Wnt co-receptor Dlp impaired in Mmp mutants. Although the precise roles of and the interplay between Mmp1, Mmp2 and Timp have yet to be fully understood, this system provides a powerful new model for investigating the roles of the matrix metalloproteome during synaptogenesis.

Pausing on the way to pluripotency

The generation of induced pluripotent stem cells (iPSCs) has revolutionised the stem cell field, opening up avenues for both basic and translational research. However, there is still much to understand about the mechanisms underlying reprogramming to the iPSC state, particularly in human. On p. 15, Takashi Tada and colleagues report the isolation of stable ‘intermediately reprogrammed stem cells’ (iRSCs) that are paused in their progression to pluripotency. These cells, generated by transient expression of the reprogramming factors Oct4, Klf4, Sox2 and c-Myc, express some pluripotency markers, such as endogenous SOX2 and NANOG, but have not yet undergone mesenchymal-to-epithelial transition (MET) or upregulated endogenous OCT4. The iRSC lines are stable over multiple generations, but can easily and efficiently be induced to continue reprogramming to an iPSC-like state by culture at high density. The authors use these iRSC lines to characterise the order of events during reprogramming, finding that in human, unlike in mice, induction of endogenous OCT4 expression precedes MET. Importantly, however, this expression is initially unstable, and some cells revert to an OCT4⁻ state and show signs of lineage commitment. These cells lines should provide a valuable tool for further investigation of the mechanisms underlying reprogramming to pluripotency of human cells.

PLUS…

Future developments: your thoughts and our plans

As a journal with its community very much at its heart, we here at Development believe it is essential to ensure we take your opinions into account when planning for the future. It was with this ethos in mind that we recently carried out a community survey looking at how well the journal reflects the current state and future directions of the field. Here, we discuss the results of this survey and the future directions of the journal. See the Editorial on p. 1

When stem cells grow old: phenotypes and mechanisms of stem cell aging

All multicellular organisms undergo a decline in tissue and organ function as they age. Here, Michael Schultz and David Sinclair discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases, lifespan and potential therapies. See the Review on p. 3

Featured movie

Our latest featured movie shows cardiac contractility and circulation near the heart of a zebrafish and is from a recent paper by Torres-Vázquez and colleagues. They performed a genetic screen in zebrafish and identified reck as a key modulator of Wnt signalling, required in the brain endothelium for intra-cerebral vascularisation and proper expression of barriergenesis markers. Read their paper: http://bit.ly/1PaUYHi

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