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During spermatogenesis, progenitor cells must undergo tightly regulated changes to produce functional gametes. However, the genetic control of this process in humans has eluded researchers. This week we feature a paper published in the latest issue of Development that describes the changing genetic expression of cell during spermatogenesis. The co-first authors Sabrina Jan and Tinke Vormer and PIs Sjoerd Repping and Ans van Pelt of The University of Amsterdam told us more.

Sjoerd and Ans, can you each give us your scientific biographies and the main questions your lab is trying to answer?

SR & AvP We work at the Center for Reproductive Medicine of the Academic Medical Center of the University of Amsterdam. Our center focusses on providing top-clinical care to patients suffering from infertility and on understanding the basic pathophysiological mechanisms underlying infertility. Our research laboratory has four active lines of research: 1- Spermatogenesis and spermatogonial stem cells, 2- Preimplantation embryo development, 3- Genomic stability of reproductive cells, and 4- Placentation and gestational diseases. Besides our laboratory research, our department is very active in healthcare evaluation research where we try to increase effectiveness and safety of medically assisted reproduction.

Sjoerd was trained as a clinical embryologist, received his PhD on genetics of male infertility at the University of Amsterdam and the Whitehead Institute in Cambridge and is currently professor of Human Reproductive Biology, head of the Center for Reproductive Medicine and Director of the Amsterdam Reproduction & Development Research Institute.

Ans was trained as a stem cell biologist. She received her PhD on the role of vitamin A on spermatogenesis and spermatogonial stem cells at the Medical School of the Utrecht University in collaboration with the Hubrecht Institute, both in the Netherlands. She is currently associate professor at the Center of Reproductive Medicine, head of the Reproductive Biology Laboratory and leader of the research line Spermatogenesis and spermatogonial stem cells.

Sabrina and Tinke, how did you both end up working on this project?

SJ I started working on this project as part of my PhD training. I have always been very interested in the field of reproductive medicine. In 2008 I completed a masters degree in reproductive and developmental biology. In 2011 I was looking to further academic training and as soon as I read this project’s research proposal I was immediately interested. For me, spermatogenesis is a unique process from which we can learn so much not only about gamete formation and fertility but also about the molecular control of processes such as stem cell biology, mitosis, meiosis and cytodifferentiation.

TV Before joining the Centre for Reproductive Medicine, I performed my PhD studies at the Netherlands Cancer Institute in Amsterdam, where I studied the molecular changes that occur when a healthy cell transforms into a cancer cell. As such, the step to studying the molecular changes during spermatogenesis is not as big as people sometimes think. During my undergraduate studies, I performed a literature study about molecular changes during spermatogenesis and I was absolutely amazed by this process. After finishing my PhD studies, I saw an advertisement for a postdoctoral position in the Centre for Reproductive Medicine, and immediately applied.

What was known about the molecular control of spermatogenesis in humans prior to your paper?

AvP The molecular control of human spermatogenesis was largely unknown. Only recently a few groups in the world have investigated the transcriptome and epigenetic patterns of the entire human testis or some isolated testicular cell types, but not to the extent as we have now been able to do.

Can you give us the key results of the paper in a paragraph?

AvP & SJ In this paper we investigated the transcriptome of male germ cells using laser capture microdissection to isolate testicular cells based on morphology and localization in the testis. By doing so, we were able to identify the RNA profiles of many more subpopulations of germ cells than with any other method described before. This resulted in a far more detailed understanding of the molecular regulation of human spermatogenesis.

TV We identified the onset of major gene expression changes during human spermatogenesis and discovered the specific timing of transcriptional changes of individual genes. Also, we found that A_dark (quiescent), A_pale (actively dividing)  spermatogonia display similar transcriptomic patterns and that the transcriptome of precursor cells already contains genes necessary for cellular differentiation later in development.

Can you briefly describe the technique you developed and how it could be used to answer other biological questions?

AvP & TV The technique is based on single cell laser capture microscopy out of fixed and paraffin embedded tissue. During this project, we learned that the fixative is of crucial importance. Not only for the recognition of various cell subtypes in the tissue based on their nuclear structure, but also to maintain RNA integrity to allow for in-depth transcriptome analyses of the isolated cells. In our case with testis tissue, we ended up with an alcohol-based fixative instead of the classically used Bouin’s fixative. This alcohol-based fixative maintains nuclear structure and RNA integrity and can be applied to any other tissue to allow for single cell capture. By using laser capture microscopy, we were able to isolate pools of single human germ cells from these alcohol-fixed specimens. This enabled us to analyse the transcriptome of human germ cells during the different stages of spermatogenesis. The technique can be used to study other tissues and developmental processes of interest.

How will your technique help future research into male infertility and possible treatments?

AvP We can now use the results of the current paper as a reference for further transcriptome analyses of germ cells from patients with a maturation arrest in spermatogenesis. In doing so, we will gather information on the molecular aberrations underlying male infertility, which will give us detailed insights for establishing future treatment strategies.

When doing the research, did you have any particular result or eureka moment that has stuck with you?

SJ A moment that will always stick with me while working on this study is the moment I saw the first sequencing results. Many had doubted if this project would be feasible considering the small amounts of RNA we were attempting to experiment with, and it indeed took us years to be able to do so. It is astonishing how much one can do with extremely small amounts of RNA (picograms) (and will power!); we were able to generate whole transcriptomic profiles. This gives new meaning to the phrase “nothing is impossible”.

TV When setting up the technique, we had to find the correct fixative, microscope settings and a reliable RNA amplification method to be able to analyse our cells using next generation sequencing. Once this all worked out and we got our first sequencing runs: great!

And what about the flipside: any moments of frustration or despair?

SJ There were certainly moments of frustration but certainly not despair. We had a period during the project in which the tubes used for laser capture microdissection were malfunctioning resulting in loss of our carefully collected germ cells. Capturing spermatogonia (germ cells that require careful microscopic evaluation) takes a long time – on a good day we captured 50 germ cells in 3-4 hours. So, you can imagine that loss of such precious collections causes a lot of frustration. Thankfully, it was a batch problem and we could easily solve this problem with the tube suppliers.

TV The isolation of single cells under the microscope is a concentrated job. Especially because we had to set up the technique, this involved quite some patience. Once an experiment failed after carefully isolating all the individual cells, this could be a very frustrating moment… Luckily, Sabrina and I could support each other!

What are your career plans following this work?

SJ At this moment I am in training to become a molecular clinical geneticist at the University Medical Center Groningen in The Netherlands. This project was inspirational in my current career path. Working on spermatogenesis, I was able to work on RNA expression but was also able to gain knowledge on the role genetics plays in the pathophysiology of spermatogenesis. This sparked my interest in genetics. Since RNA expression is a growing field in genetics, in my current work I get to merge these two very interesting worlds together.

TV I am currently working as a medical science liaison for a pharmaceutical company. The research for this paper was performed in close collaboration with physicians that treat infertile patients. I found this very inspiring and hope that our work will contribute to the development of future treatment strategies. In my new role, I am close to the development and application of new therapeutics in the clinic and have regular contact with physicians, which I find very rewarding.

What’s planned next for the Repping and van Pelt labs?

SR & AP One of the most exciting things we are working on is bringing autotransplantation of spermatogonial stem cells (SSCs) into clinical practise for sterile childhood cancer survivors. Often children with cancer become sterile due to the chemotherapy they receive to treat  their cancer. We have pioneered the development of an in vitro culture system of human SSCs and are currently in the progress of finalizing crucial in vitro and animal safety studies before we embark on the first clinical trial in humans. Furthermore and in line with the current study, we aim to study the molecular aberrations in men suffering from idiopathic infertility. The ultimate goal there would be to treat these men with a therapy, perhaps in combination with SSC autotransplantation, that will allow these men to produce sperm again and become a genetic parent.

Lastly, what do each of you like to do when you’re not in the lab?

SR I enjoy taking long distance runs (just ran my 6^th marathon), reading and spending time with my family and friends.

AvP I enjoy hiking, cycling and spending time with my family and friends.

SJ I enjoy going out dancing with my friends, swimming and various other activities such as walking in the various different beautiful dunes in The Netherlands and last but certainly not least, spending time with my family.

TV I am a big fan of flamenco dancing! I have been doing that for quite a few years, and I recently started with a flamenco-singing class for dancers. It is a lot of fun, I really enjoy the musicality and temperament of this music. Of course I also enjoy spending time with family and friends.

Sabrina Z. Jan, Tinke L. Vormer, Aldo Jongejan, Michael D. Röling, Sherman J. Silber, Dirk G. de Rooij, Geert Hamer, Sjoerd Repping, Ans M. M. van Pelt. 2017. Unraveling transcriptome dynamics in human spermatogenesis. Development. Volume 144, Issue 20, p3659-3673.

This is #30 in our interview series. Browse the archive here. 

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The Copenhagen Bioscience PhD programme recruits up to 16 motivated international students annually to launch their careers in the vibrant scientific environment of the Novo Nordisk Foundation Research Centers in Copenhagen. For enrollment in September 2018, applications is now open until December 2017.

Selection is based on academic achievements, research experience, academic references and interviews. A mandatory interview visit for up to 40 shortlisted applicants comprises panel interviews, one-on-one meetings with potential supervisors, and tours of the four Novo Nordisk Foundation Research Centers, and will take place in Copenhagen in March 2018. The Novo Nordisk Foundation will pay for travel and accommodation for selected applicants in association with the interview visit.

Find out more and apply: http://novonordiskfonden.dk/en/content/copenhagen-bioscience-phd-programme

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The University of Manchester, 2018/19 BBSRC DTP PhD Project

Understanding tubulin regulation during neuronal development, ageing and degeneration

Axons are slender, up-to-a-meter long, cable-like extensions of neurons which form the nerves and nerve tracts that wire our bodies and brain. These delicate cellular structures have to be maintained for an organism’s life time and are often the first to be affected in ageing, injury and neurodegeneration. To understand such conditions and identify ways to improve axon maintenance and regeneration, we study the regulation of microtubules (MTs) which form parallel bundles running all along axons to form their structural backbones and life-sustaining transport highways.

 

On this project, you will study how the polymerisation of MTs within these bundles is regulated to drive axon growth and prevent senescence during ageing. The key question is how tubulins (i.e. the building blocks of MTs) are made available and continuously supplied in the narrow axons, up to a meter away from the cell body. This fascinating topic is most relevant to axon biology and pathology but surprisingly little understood. Your pioneering work will be based on our recently published mechanistic model of axonal tubulin supply and MT polymerisation, deduced from our own data and general knowledge in the field [Ref.1]. You will use cutting edge methodologies to study (1) contributions made by axonal transport and local tubulin translation, (2) roles of the chaperone machinery of tubulin assembly, and (3) mechanisms of tubulin storage and gene expression regulation.

 

For your studies, you will use neurons of the fruit fly Drosophila, which provide uniquely powerful genetic and cell biological means in order to efficiently generate new understanding that can then be applied to higher animals [Ref.2; LINK]. You will be able to capitalise on expertises of the supervisory team: the host group (Andreas Prokop) has long-standing experience with MT regulation and the Drosophila neuron model, the first co-supervisor’s group (Thomas Waigh) with high resolution imaging and quantitative approaches [Ref.3; Ref.4], and the second co-supervisor’s group (Mark Ashe) with RNA visualisation and processing [Ref.5].

 

Your transferable and experimental skill training will include genetics, cell biology, molecular biology, imaging techniques (live, high resolution, axonal transport, spatial detection of RNA and translational activity), quantitative analyses and modelling, as well as expertise in the important research areas of cytoskeleton and neurobiology. Finally, Andreas Prokop is an expert in science communication [Ref.6] providing further training opportunities important for your future career.

Information and applications:

• For more information, contact Prokop@manchester.ac.uk
• To find the project, go to this LINK (search for “Prof. Prokop” in the supervisor field)
• To apply, go to this LINK
• Deadline for applications is Fri 2nd of Nov. 2017, 5pm
• Interviews are held on Tue/Wed, 9th/10th Jan. 2018
• Offers will be confirmed in mid-Feb. 2018

References

[1] Voelzmann, A., Hahn, I., Pearce, S., Sánchez-Soriano, N. P., Prokop, A. (2016). A conceptual view at microtubule plus end dynamics in neuronal axons. Brain Res Bulletin 126, 226-37

[2] Prokop, A., Beaven, R., Qu, Y., Sánchez-Soriano, N. (2013). Using fly genetics to dissect the cytoskeletal machinery of neurons during axonal growth and maintenance. J. Cell Sci. 126, 2331-41

[3] Kenwright, D.A., Harrison, A.W., Waigh, T.A., Woodman, P.G., Allan, V.J. (2012) First-passage-probability of active transport in live cells, Physical Review E, 86, 031910

[4] Georgiades, P., Allan, V.J., Dickinson, M., Waigh, T.A. (2016) Reduction of coherent artefacts in super-resolution fluorescence localisation microscopy, Journal of Microscopy, 264, 3, 375-383

[5] Sfakianos, A. P., Whitmarsh, A. J., Ashe, M. P. (2016). Ribonucleoprotein bodies are phased in. Biochemical Society Transactions 44, 1411-1416

[6] Illingworth, S., Prokop, A. (2017). Science communication in the field of fundamental biomedical research

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T. Thomson Flynn and J.P. Hill. 1939. The Development of the Monotrema – Part IV. Growth of the Ovarian Ovum, Maturation, Fertilisation and Early Cleavage. Transactions of the Zoological Society of London, 24, 445-623.

T. Thomson Flynn and J.P. Hill. 1947. The Development of the Monotrema – Part VI. The Later Stages of Cleavage and the Formation of the Primary Germ-layers. Transactions of the Zoological Society of London, 26, 1-151.

Recommended by Guojun Sheng, IRCMS, Kumamoto University, Japan. 

Mammals alive today are split into three groups: the placentals (like us), the marsupials (like Skippy), and, distantly related to the rest, the monotremes. Monotremes come in two kinds: echidnas, “shambling, animated pincushions” whose young are known as ‘puggles’, and platypuses, famous for their chimeric collection of weird anatomical features (their species name, Ornithorhyncus anatinus, means ‘duck-like bird-snout’).

In addition to their odd appearance, monotremes stand out compared to other mammals when it comes to reproduction: rather than giving birth to live young, they lay eggs, a trait shared with birds and reptiles, which together form the sister group to mammals (mammals, birds and reptiles together form the amniotes). Given their phylogenetic position and mix of biological traits, monotremes might tell us a lot about mammalian evolution from a reptile-like ancestor, keeping in mind of course that they have not stayed still since they split from the rest of the mammals perhaps a hundred and sixty million years ago. From the perspective of developmental biology, the question is how an ancestral, reptile-like mode of embryogenesis was transformed into a mammal-like one: do monotremes develop more like other mammals, or more like birds and reptiles? (Another proviso here: ‘mammal-like’ rather obscures the diversity seen in early mammalian embryogenesis, as explored by Guojun Sheng, Marilyn Renfree, Berenika Plusa and others, but monotremes might in fact prove a useful example to understand this diversity.)

Answering these questions is not easy. Some animals are more amenable to embryological investigation than others, and monotremes are exceptionally intransigent in this regard: they can be hard to find, do not breed well in colonies (though this might be getting easier), are not really prodigious breeders in any case, and have embryos that are difficult to collect and preserve. ‘Non-model’ doesn’t quite cover it.

Nevertheless, monotreme embryology has a long history. The Scottish zoologist W.H. Caldwell was one of first Western scientists to unequivocally describe monotreme egg-laying (read more in Brian Hall’s paradoxical history of the platypus), in a famously terse telegram sent while on an expedition in Queensland in 1884 :

“Monotremes oviparous, ovum meroblastic”

‘Meroblastic’ describes the incomplete cleavage of the early embryo, which reptiles and birds do too.

Caldwell’s expeditions were torrid affairs –

“Crossing the Maclntyre River in a flood, the buggy was upset, and its contents washed away. The two following months were lost through the effects of a fever…”

But not just for him: the Aboriginal Australians employed  by Caldwell to catch the animals were treated horrendously, according to the introduction to his paper describing the expedition (it’s quite a shocking read, but perhaps not an altogether surprising one).

As Caldwell describes, collecting monotreme samples in the wild was a difficult and often brutal business. Since a lot of embryonic development occurs in utero, to get earlier stages you have to kill the mothers. Platypuses posed particular problems, as described in a later account:

“…it is extremely difficult, even for residents in Australia, to procure material necessary for an investigation into the development of the egg of Ornithorhynchus….The animal itself, though pretty widely distributed, and probably still far from becoming extinct, is to be found, in any one locality, only in comparatively small numbers.

The eggs, when laid, are deposited in a burrow which it is far from easy to locate, and whose opening up involves a considerable amount of labour, since, apart from its great length, the river-bank in which it is situated is commonly enough permeated by tree-roots. And when at length the actual dwelling-chamber or nest is successfully opened up, no reward at all may be forthcoming, or the material which is obtained may be unsuitable for the immediate purpose in view.

Even when it is the intra-uterine stages of the egg which are required…the difficulties are nearly as great. The animal is extremely shy and difficult [to] approach. They are occasionally, but rarely, captured as an incident in net-fishing in the larger rivers: otherwise they are practically only obtainable with the gun. During the breeding season, however, the pregnant female appears to keep much more closely to the burrow, so that one may then commonly enough shoot five or six males to one female.”

This was published in 1908 by J.T Wilson and one J.P. Hill, who with T.T. Flynn wrote the two hefty monographs that are the subject of this Forgotten Classics piece – Volume IV and Volume VI of the Transactions of the Zoological Society of London’s Development of the Monotrema series.

Hill was born in Edinburgh but moved early in his career to Sydney (where he met Flynn who was studying there), before returning to the UK to University College London and rising to chair of embryology and histology. Flynn was an Australian who moved to Tasmania from Sydney to become a professor of biology and an eminent naturalist. In Tasmania, as well as collecting monotreme samples, he fathered Errol Flynn (yes that Errol Flynn, the actor), but after his funding was cut he moved to Queens University in Belfast. There he served as a fire martial and casualty clearing officer in the Second World War, for which he was awarded an MBE.

The two monographs describe observations on a collection of 150 or so monotreme eggs and embryos initiated in 1896 by Hill in Queensland, and later added to by Flynn in Tasmania. The samples were preserved in the field and then sectioned, stained and analysed in the lab, often decades later (one was embedded in wax thirty years before being sectioned with a myotome; there may have been half a century between a sample’s collection and the publication of its description). Volume IV describes the making of the monotreme oocyte, its fertilisation and the early cleavage stages of the embryo. Volume VI goes from cleavage until germ layer formation.

The monographs are methodical and descriptions of the collection – each sample is described in the most minute of details, consistent with Hill’s renown for accuracy both in sample preparation and description (“everything he does is done with the most meticulous accuracy…the exact wording of each sentence had to be discussed to make certain that it was precise, unambiguous, and made all possible reservations”, according to the introduction to a dedicated volume of the Journal of Anatomy). It can make for some daunting reading, particularly if you are unfamiliar with some of descriptive terms – one section on the oocyte features eosinophil and basal granules, pseudo-reticular strands, vitello-fatty zones, irregular sinuous folds, linin threads. But in fact much of it is written beautifully and the plates are often quite stunning.

Playpus oocyte. Figure 34, Plate VII, Flynn and Hill, 1939.

Echidna, section through the follicular wall. (f.s. = follicular secretion ; zp = zona pellucida; th.e. & th.i., = theca externa and interna; f.e. = follicular epithelium). Fig. 70, Plate XIV, Flynn and Hill, 2939.

Echidna. Section of germinal disc, showing the male and female pronuclei overlapping each other at the centre of the formative zone of the disc (fcd). (vcd. = deep vacuolated zone of the disc; mg.x. = marginal zone; shm. = shell-menibram; yb. = yolk-bed; zpa. = zona-albumen layer.) Fig. 77, Plate XV, Flynn and Hill, 1939.

Echidna, showing male and female pronuclei together. Figure 81, Plate XV, Flynn and Hill, 1939.

Platypus, 8 cell stage, showing mitosis. Figure 96, Plate XVIII, Flynn and Hill, 1939.

Echidna blastodisc, transverse view. (gr. = germ-ring; pv. and smv. = peripheral and sub-marginal vitellocytes). Fig. 56, Plate IX, Flynn and Hill, 1947.

Echidna blastodisc, surface view. Fig. 67, Plate XI, Flynn and Hill, 1947.

Echidna, showing a portion of the unilaminar blastodermic membrane (emc = endodermal mother-cell; p.ect. = prospective ectoderm cell). Fig. 99, Plate XVII, Flynn and Hill, 1947.

So how do you make a monotreme? Flynn and Hill observed that many features of monotreme oocyte formation and embryogenesis look quite like their bird and reptile cousins. For instance the eggs are yolky, the germinal disc sits on top of the yolk, and early cleavages are meroblastic; early cleavage creates a cellular blastoderm that is separate from the uncleaved yolk; there is an extra-embryonic structure called a germ-ring not seen in mammalian embryos; the multi-layered blastoderm thins out into a single layered structure, and this process appears to involve migration of cells to within the embryo, which looks like reptile delamination. There are also some features that are more mammal-like, and some which seemed to Flynn and Hill to be unique to monotremes, but the key observations seem to be that these mammals share a lot of features of early embryogenesis with birds and reptiles.

As discussed by Guojun Sheng below, Flynn and Hill’s findings suggest we should do more to understand the early development of birds and reptiles, stages which have historically, and for technical reasons, been underserved. We could then move to a more complete understanding of the variations of amniote development, and hence its evolution.

The work also makes us consider the use of different models in developmental biology. There are many animals for which descriptive embryology and anatomy of the kind practised by Flynn and Hill was the only way in, and for which today perhaps only genome sequences – the platypus genome was sequenced in 2007 – can add to our understanding. When such animals are the only extant outcomes of critical evolutionary junctures, papers like Flynn and Hill’s are crucial. And, of course, we are benefiting from work that was of its time: such a collection with its collateral damage of thousands of dead monotremes simply could not have been assembled today. No one has performed a similar analysis since, so the papers really do stand alone in embryology.

But the story isn’t over, at least for echidnas: the establishment of colonies promises to provide additional opportunities to understand monotreme development, and there are even PhD positions available! For now at least, I’d like to propose a monotreme wing in William Sullivan’s Institute for the Study of Non-Model Organisms.

Thoughts from the field

Guojun Sheng, IRCMS, Kumamoto University, Japan

These two related, heavy-weight (literally) papers by the same authors (TT Flynn and JP Hill) [for biographical accounts, see http://adb.anu.edu.au/biography/hill-james-peter-6669 and http://adb.anu.edu.au/biography/flynn-theodore-thomson-6202 ] describe pre-gastrulation development of monotreme embryos. Despite the length (each over 150 pages), these two papers are easy and enjoyable to read. The clarity and quality in their writing style and data presentation can only be appreciated by reading the original papers, rather than from summaries in a handful of review papers which cited them.

What makes them essential readings for developmental biologists is their relevance to modern-day stem cell biology, the foundation of which is based on our understanding of mammalian early development. The monotremes are a group of prototherians (early-branched out mammals) which retain many developmental features of their reptilian ancestor. Our knowledge on cellular and molecular regulation of early lineage segregation (trophoblast, epiblast and hypoblast) in eutherians (placental mammals including mice and humans) would be incomplete, to say the least, without an understanding of these events from the perspective of comparative mammalian/amniote embryology. Although experimentation with monotreme embryos is impractical, similarities between monotreme and reptilian (including avian) early development make a strong case for redoubling our efforts in the investigation of pre-gastrulation development using avian/reptilian models.

Readers may be interested in two papers from our lab:

1) Research paper on chicken pre-ovipositional development (published in Development)

http://dev.biologists.org/content/142/7/1279.long

2) Review paper on comparative amniote pre-gastrulation development (published in Developmental Biology)

www.sciencedirect.com/science/article/pii/S0012160614005193

Both papers have been made free to view for three months courtesy of Wiley Publishers.

Aidan Maartens

This post is part of a series on forgotten classics of developmental biology. You can read the introduction to the series here and read other posts in this series here. We also would love to hear suggestions for future Forgotten Classics – let us know in the comments box.

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Supervisors: Dr Jill Harrison and Dr Martin Homer.

Plant shapes range from tiny string or mat-like forms to massive multilayered upright forms with complex organ systems such as shoots, roots and leaves. Despite these wide differences in shape, many plant gene families are very ancient, predating shape diversification. We can therefore study mechanisms for shape determination in simple plants such as liverworts, and use the knowledge gained to understand plant shape determination in general.

To this end, we previously used a combination of live imaging, statistical model fitting, computational modelling and molecular biology to discover mechanisms regulating shape in the liverwort Marchantia polymorpha (Solly et al. (2017): Current Biology).

We found that Marchantia undergoes a stereotypical sequence of shape transitions during development. The overall shape depends on regional growth rate differences that are specified by the growing apical notches. Computational modelling showed that a diffusible, growth-promoting cue produced in the notches is likely to pattern these regional growth rate differences, and pharmacological experiments suggested that the plant hormone auxin equates to this growth-promoting cue.

New models suggest a role for differential oriented growth (anisotropy) in Marchantia shape determination. Anisotropy emerges as an outcome of underlying tissue polarities, and directional auxin transport may have a role.

Your project will build on the work above to determine how auxin contributes to plant shape determination in Marchantia.

Training:

By combining computational and wet lab approaches, your project work will provide training at the cutting edge of the plant evolution and development fields. You will benefit from further formal teaching and internships included in the SWBioDTP programme. The skills and techniques you learn will be broadly applicable in the academic biology and biotech sectors and widely transferable amongst areas such as science policy, publishing and computing.

Reading:

Harrison (2017). Development and genetics in the evolution of plant body plans. Philosophical Transactions of the Royal Society B 372: 20150490.

Hong and Roeder (2017). Plant development: differential growth rates in distinct zones shape and ancient plant form. Current Biology 27: R19-21.

Solly et al. (2017). Regional growth rate differences specified by apical notch activities regulate liverwort thallus shape. Current Biology 27: 16-26.

Whitewoods and Coen (2017). Growth and development of three-dimensional plant form. Current Biology 27: R910-918.

Further information:

The deadline for applications is 4th December 2017. Please contact Dr Jill Harrison (jill.harrison@bristol.ac.uk) for informal discussions about the project. Further information about project supervisors’ work can be found on Jill Harrison and Martin Homers’ home pages. Further information about the SWBioDTP and application procedures is listed on the SWBioDTP web pages.

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Supervisors: Dr David Ferrier (University of St Andrews) and Prof Kate Storey (University of Dundee)

This project will dissect the regulatory mechanisms of the chordate ParaHox genes (Gsx, Xlox/Pdx1 and Cdx), analysing regulatory elements of these genes in both the invertebrate sea squirt Ciona intestinalis and the vertebrate Gallus gallus (chicken). ParaHox genes are the evolutionary sisters to the Hox genes, and like their sisters are important components of axial patterning, mainly in the central nervous system and gut. They also tend to have a clustered organisation in the genome that is likely linked to how the genes are regulated. Mis-regulation of ParaHox genes can cause diseases such as diabetes and colon cancer, and changes to the Hox/ParaHox genes are important agents in the evolution of animal form.

In this project, we will capitalize on the power of the comparative approach to deduce underlying fundamental aspects of body axis patterning by regulation of the ParaHox genes.

The student will obtain training in cutting-edge techniques in molecular biology, embryology, bioimaging and bioinformatics and be part of the enthusiastic and vibrant research communities in the Universities of St Andrews and Dundee, benefitting from the complementary strengths, strong links and close proximity of these institutions.

Funding Notes

Applications for BBSRC EASTBIO studentships are invited from excellent UK students (and EU citizens if they meet UK Research Council residency criteria) with at least a BSc (Hons) 2.1 undergraduate degree.

More information.

e-mail: dekf@st-andrews.ac.uk

https://www.findaphd.com/search/ProjectDetails.aspx?PJID=90025&LID=1443

How to apply?

https://synergy.st-andrews.ac.uk/research/phd-study/

Application deadline: 4^th December 2017.

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Here are the highlights from the current issue of Development:

Sequencing sheds light on human spermatogenesis

In order to produce sperm, progenitor germ cells in the testes must undergo mitosis, meiosis, differentiation, and alter their chromatin structure to give rise to functional gametes. Much of our knowledge about how this complex process is controlled in humans is extrapolated from studies performed on mice, despite the fact that spermatogenesis may differ between species. On p. 3659, Sjoerd Repping and colleagues combine laser-capture microdissection and next-generation RNA sequencing techniques to provide the first detailed analysis of the gene expression patterns of spermatogenic cells isolated from human tissue. They profile the transcriptomes of six functionally distinct classes of germ cells from the human testis, which represent successive steps in the process of spermatogenesis. They find that over 4000 genes are dynamically transcribed throughout this process, including a significant number of post-transcriptional regulators such as RNA-binding proteins and long non-coding RNAs. These data suggest that post-transcriptional regulatory mechanisms are important for the transition of germ cells from a precursor state into differentiated sperm. This work provides valuable insight into how the process of sperm production differs between humans and other species at a transcriptional level, and should serve as an important resource for identifying genes implicated in male infertility.

miR-290: the making of placental mammals?

MicroRNAs play a variety of roles during development, primarily by regulating gene expression through repression of target mRNAs. One cluster, the miR-290 cluster, is specific to placental mammals, and has, in the past, been linked to pluripotency maintenance in the early mammalian embryo. On p. 3731, Robert Blelloch and colleagues now uncover a role for the miR-290 cluster in placental development. Using transgenic mouse lines, they find that the miR-290 cluster is highly expressed during early mouse embryogenesis and becomes restricted to the trophoblast from gastrulation up until birth. When the miR-290 cluster is deleted, mRNAs targeted by this cluster become dysregulated. Interestingly, this deletion also causes several placental defects, including a reduction in trophoblast proliferation, reduced giant cell endoreduplication, and disruption of the vasculature of the placental labyrinth. Ultimately, this results in the development of a placenta that is reduced in size, and defective in passive diffusion of nutrients from the mother to the foetus, leading to late embryonic lethality. These results suggest that microRNAs within the miR-290 cluster are responsible for regulating the gene network important for placental growth and development in mice, and may provide insight into the evolution of eutherian mammals.

Semaphorin marks the spot in the pancreas

Islets are clusters of endocrine cells in the pancreas that contain specialised cell types responsible for the secretion of hormones such as insulin and glucagon. During the development of the pancreas, progenitors of islet cells delaminate from the embryonic ductal epithelium then migrate before maturation, so that the endocrine cell clusters become scattered throughout the pancreatic tissue. On p. 3744, Seung K. Kim and colleagues now uncover a mechanism controlling the migration of these cells and the subsequent positioning of islets. Using transgenic mouse lines and protein-soaked beads, they identify the semaphorin ligand Sema3a as a long-range guidance signal for migrating foetal islet cells. They show that endocrine cells express high levels of the Sema3a receptor neuropilin 2, allowing them to sense and transduce this chemoattractant. Intriguingly, this mechanism is similar to that which controls neuronal migration in the developing brain, and thus uncovers a conserved mechanism for directing the migration of progenitor cells during organogenesis.

Decisions, decisions: cell fate choice in the early mammalian embryo

During the first week of mammalian development, the cells of the early embryo undertake two sequential cell fate decisions and segregate into the three lineages that make up the blastocyst. First, the trophectoderm (the precursor tissue to the placenta) becomes specified, occupying the outside of the embryo and surrounding uncommitted inner cell mass (ICM) cells. These subsequently segregate to Nanog-expressing epiblast (EPI; the embryo proper) and Gata6-expressing primitive endoderm (PE; yolk sac precursors).

In this issue, two research articles, one from the Ema lab and the second a collaboration between the Plusa and Piliszek labs, delve deeper into what governs the crucial EPI/PE cell fate specification event, which is well known to be reliant on FGF/ERK signalling. On p. 3706, Masatsugu Ema and colleagues provide evidence that the transcription factor Klf5 lies upstream of FGF/ERK signalling. They find that Fgf4 is upregulated in Klf5-knockout mouse embryos, which fail to specify EPI and can only generate PE. Conversely, when Klf5 is overexpressed, ICM cells fail to segregate, and continue to co-express both Nanog and Gata6. Furthermore, they find that Klf5 binds to the Fgf4 locus, suggesting that Fgf4 expression can be directly regulated by this transcription factor.

In the second study (p. 3719), Anna Piliszek et al. use a different model system – the rabbit – to investigate lineage specification in early embryos. Unlike the mouse embryo, they detect co-expression of NANOG and GATA6 in late blastocysts, suggesting that mutual co-repression does not function in the initiation of lineage specification in rabbit. Furthermore, they show that inhibition of FGF signalling is not sufficient to expand the population of EPI cells, and although the population of PE cells is reduced, GATA6 expression is unaffected. These results indicate that although the key transcription factors are conserved in early mammalian embryogenesis, the way they function, and the way they interact with signalling pathways, may differ between species.

Taken together, these data add to our understanding of how the earliest cell fate decisions are taken in the mammalian embryo, and how they vary across evolution.

Plus…

Mitotic bookmarking in development and stem cells

This Primer provides an overview of mitotic bookmarking processes in development and stem cells, highlighting how bookmarking factors can regulate cell identity and contribute to phenotypic flexibility and plasticity during development.

The three-dimensional genome

This Review summarizes the role of 3D chromatin architecture in organizing the regulatory genome and evaluates how its misfolding can lead to gene misexpression and disease.

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We are accepting candidates for a postdoctoral research associate in our multidisciplinary research group. The Clark group at Northeastern University detects ions (Na, K, Ca, etc.) and small molecules (glucose, acetylcholine, etc.) as well as proteins, and we are working with the Monaghan group in Biology to detect chemicals in vivo.  In particular, we are seeking to fill two positions on a project to image acetylcholine release in the peripheral nervous system. The successful candidate would be highly motivated and have a strong background in fluorescence imaging, particularly in vivo.

For more details, please follow the link:

http://neu.peopleadmin.com/postings/51277

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The International Max Planck Research School for Translational Psychiatry (IMPRS-TP) is offering PhD positions in molecular, cellular and systemic psychiatric research. Students are exposed to a wide range of scientific questions and methods covering areas of molecular medicine, neuroscience, psychiatry, quantitative epigenetics and imaging, neuroimaging, design-based stereology and clinical studies.

Research in a translational setting 

In addition to the traditional doctorate positions, trainee medical doctors are given the opportunity to be enrolled on an integrated PhD/residence program in psychiatry. Highlighting the translational facet, doctorate students will receive insights into clinical aspects of disease and trainee medical doctors will gain PhD level research expertise, while also developing their clinical skills.

Receive exceptional training for a successful career in research, clinic and academia! 

Structured curriculum: Core Course | Lecture Series | Methods Workshops | Soft Skills

Topics addressed range from molecular and cellular neuroscience, behavioral assessments, electrophysiology and brain imaging to psychological and clinical measures and outcomes, as well as, epidemiology, statistics and bioinformatics.

Work in an environment of scientific excellence and interdisciplinary collaboration 

IMPRS-TP is a joint initiative of leading scientists from the Max Planck Institutes of Psychiatry and of Neurobiology and the Ludwig Maximilians University, Munich. Further collaborations have been established with the Munich Medical Research School (MMRS), the Helmholtz Center Munich, the Graduate School of Systemic Neurosciences (GSN), Martinsried, Germany and King’s College London, UK. IMPRS-TP is co-funded by the Else-Kröner-Fresenius Foundation.

Call for applications 

IMPRS-TP welcomes applications from doctoral candidates coming from any country who hold a 4 year Bachelor or Master of Science (or an equivalent degree) in a relevant field or a Medical Degree. Applications from trainee medical doctors with laboratory experience are particularly encouraged. IMPRS-TP will only accept applications submitted through the IMPRS-TP online application tool. Applications submitted by mail or email will not be considered. Application deadline is January 2nd, 2018.

For more information, visit http://www.imprs-tp.mpg.de/ 

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