4WH Neurogenesis: What Where Why When and How?

Neurogenesis is understood as the process by which neural stem cells (NSCs) produce new neurons. In the adult mammalian brain, this process is known to persist in two restricted locations- the dentate gyrus (DG) region of the hippocampus (see figure below) and the lateral walls of the subventricular zone (Ming and Song, 2011). Neurogenesis has been reported to occur at a high pace during embryonic development, decrease rapidly during growth and maturity, and persist in the adult brain at very low levels. New born neurons in the mature brain have been affiliated with important functions including learning, memory and damage repair.

Currently, researchers are focused on dissecting the mechanisms of neurogenesis in the adult brain to understand its unique self-repair strategies, which in turn have the potential to combat a variety of challenging neurodegenerative disorders. But do we know enough? Realistically, this is just the start of a new era in regenerative medicine, and the ‘Adult Neurogenesis 2018’ conference had just taken us a couple steps forward by showcasing cutting-edge research progress in this field.

Adult Neurogenesis 2018 was organised by Gerd Kempermann in collaboration with Abcam in the beautiful city of Dresden. The meeting was held in at the Center for Regenerative Therapies Dresden (CRTD) (see figure below) which currently hosts eighteen core groups in a network of 87 principal investigators from diverse research institutes on the Dresden campus, with expertise in biomedical fields extending from the biology of cells and tissues to biomaterials to nanoengineering. Gerd welcomed us all and initiated the meeting with a refreshing narrative, briefing us about what history has taught us, where we are headed, and the reason behind the field of adult neurogenesis.

That adult neurogenesis occurs throughout life in mammals including humans has been confirmed by multiple studies and regularly published articles following Joseph Altman and Gopal Das’s original discovery over 50 years ago (Altman and Das, 1965). However, from Santiago Ramón y Cajal’s 90 year old harsh decree of adult brain being devoid of any neurogenesis (Cajal, 1991) to Arturo Alverez-Buylla and colleagues’ 2018 description of undetectable levels of neurogenesis in the adult human hippocampus (Sorrells et al., 2018), the field of adult neurogenesis has faced its fair share of obstacles (Kempermann et al., 2018).

There is a growing need not only to unravel the mystery behind adult neurogenesis, but also  to develop technology that can provide universal and undeniable proof of its very nature, including its existence and features. Kempermann used these key facts to redefine the impact, importance and purpose of adult neurogenesis.

The Adult Neurogenesis 2018 meeting brought together some of the most influential and inspiring minds in the field of neurogenesis including, but not limited to, F. Gage, S. Jessberger, B. Berninger, S. Thuret, A. Schinder, L. Barry-Cuif, F. Calegari and M. Brand. It hosted a total of 24 talks and showcased 98 posters (see figure below) which allowed researchers from various parts of the world to share and connect with each other.

The meeting provided excellent networking opportunities allowing interdisciplinary collaboration which will ultimately lead to increase in pace and quality of scientific research. Therefore, the very existence of the meeting itself, paved a path towards finding the answer to when and how are we going to able to understand and uncover the potential of adult neurogenesis. In this report, I have managed to highlight some of my personal favourites, which undoubtedly does not cover the entirety of topics covered in the meeting.

Heterogeneity: Similar but not identical

The beauty of adult neurogenesis lies in its complex diversity. Our brain contains different types and subtypes of neuronal and glial cells all with unique functions. Moreover, depending upon factors including temporal intracellular gradients, time of birth, localisation and differences in synaptic connections, cells expressing identical protein markers in the brain can show significantly varied functions. Fortunately, recent discoveries highlighting the in-depth heterogenic nature of the immature cells involved in adult neurogenesis have begun to elucidate some of the most challenging questions regarding complexity.

Vijay Adusumilli highlighted the heterogeneity within nestin expressing NSCs of the hippocampus at a given time. Nestin is a prominent NSC marker in vivo as well in vitro. Interestingly, nestin positive DG NSCs can themselves be split into groups based on their intracellular reactive oxygen species (ROS) content. His observations emphasised how intricate differences between NSCs can produce functional diversity of neurogenesis in our brain.

Jason Snyder provided us with details on differences and relationships between adult-born and developmentally-born neurons in the hippocampus. Snyder found that changes in adult neurogenesis were inversely proportional to the activity of developmentally-born neurons. He hypothesized that the interplay between adult and developmentally-born neurons plays an important role in the acquisition and turnover of information in the hippocampus.

Alejandro Schinder gave a refreshing introduction to the intricate neuronal connections of granule cells (GCs) in the DG of the hippocampus. His lab had previously demonstrated that immature GCs of DG undergo biased neuronal activation compared to mature neurons (Marín-Burgin et al., 2012), in contrast to other regions of the hippocampus and neocortex. This functional heterogeneity between mature and immature GCs provides insights into their possible role as pattern integrators and differential decoders of information in the DG.

Together, these talks gave us an idea of how heterogeneity within NSCs, and between NSCs and new born neurons, are key factors to consider during future research in translational neuroscience.

Control or to be controlled?

Expanded research in adult neurogenesis has not only helped us provide an unprecedented surveillance of brain development but has also given us a chance to repair brain damage. Since NSCs are known to be the fundamental units of brain regeneration, recent studies have focused on modulating their behaviour and thereby developing possible therapeutic strategies for neurodegenerative disorders. This meeting was able to showcase some of the important and newly discovered modulators of adult neurogenesis.

• How is it controlled?

Autophagy is an intracellular degradation system for cytosolic proteins and organelles, which is critical for cellular homeostasis (Nixon, 2013). Iris Schäffner and her colleagues investigated the FoxO family of transcription factors with respect to regulation of autophagy in adult hippocampal neurogenesis. Schäffner hypothesized a novel pathway connecting FoxO-dependent autophagic flux to development of adult hippocampal neurons.

Tara Walker talked about how the number of new born DG neurons are kept in check. Regulation of DG neurogenesis involves the death of the majority of new born neurons. She hypothesized that a population of early hippocampal precursor cells die due to ferroptosis, an alternative form of cell death, and thus identified an additional mechanism by which adult hippocampal neurogenesis could be controlled.

Sandra Wendler was able to identify distinct roles of mitochondrial fusion dynamics in the lineage of adult NSCs in the hippocampus. Wendler was able to show that although mitochondrial fusion was dispensable for the proliferative steps of NSCs, this process becomes essential for the maturation and survival of neurons later on.

Sebastian Jessberger shared his discoveries on molecular mechanisms underlying neurogenesis with respect to lipid metabolism. He showed that Fasn, a key enzyme in de novo lipogenesis, was highly active in NSCs (see figure below) (Knobloch et al., 2013). His results provided functional coupling between regulation of lipid metabolism and adult NSC proliferation.

Taken together, these talks provided some key examples of how adult neurogenesis is controlled in the brain. A complete picture of the intricate mechanisms underlying neurogenesis are still unknown. However, piece by piece, we have started understanding the secrets of how new born neurons are created and regulated.

• How can we control it?

Georg Kuhn introduced physical exercise and enriched environment as modulators of adult neurogenesis. Kuhn explained how cardiovascular fitness and exercise are particularly important for prevention, delayed-onset or amelioration of CNS diseases including stroke and dementia (Åberg et al., 2009; Naylor et al., 2008). In parallel, Nora Abrous showed that spatial learning remodels not only new dentate neurons but also creates short term new networks within the hippocampus and long term new networks that extend beyond the hippocampus itself.

Moving deeper in a biological perspective, David Petrik showed how cells regulating adult neurogenesis are responsive to mechanical forces at the tissue level. Increased fluid flow along the walls of the lateral ventricle increased the proliferation of NSCs and this ability was dependent on Epithelial Sodium Channel (ENaC) (Petrik et al., 2018). The flow also controlled calcium oscillations in NSCs on the lateral wall, but not at a deeper niche depth, depicting specific spatial control of neurogenesis by fluid flow.

Federico Calegari took it to the cellular level, exploring whether or not  cognitive impairment could be reversed in old age or compensated throughout life by extrinsically exploiting endogenous NSCs. His lab had previously developed a system that allowed temporal control of cdk4–cyclinD1 overexpression to control the number of neurons produced in vivo (Artegiani et al., 2011). This showed, for the first time, that neurogenesis can be controlled in an acute spatio-temporal manner that allowed to elucidate and control adult neurogenesis.

Taken together, these talks provided examples of how control can be imposed upon neurogenesis in the mammalian brain, both extrinsically and intrinsically. Following on, recent studies have started screening for factors that act as master regulators of NSC homeostasis to understand the extent to which we can control neurogenesis.

The truth to be told

The ultimate objective for unfolding the mysteries and unlocking the potential of adult neurogenesis is to provide a better quality of human life. However, due to the restricted localisation and diluted potential of adult neurogenesis in mammals, not to mention to the lack of human subjects, cellular regenerative therapies for the human brain is proceeding at a considerably slow pace. The conference addressed this issue by showcasing novel technological developments and innovative adaptations of pre-existing biomedical tools which can directly increase the speed and quality of discovery with respect to clinical translation.

Studying the properties of neurogenesis can have significant indirect benefits to clinical medicine. Sandrine Thuret talked about how differential neurogenesis can be used as a biomarker to detect the fate of disease pathology in humans. Her lab showed that differential response of NSCs to patient specific serum can be extended to predict conversion of mildly cognitive impaired patients to Alzheimer’s disease (AD) (Maruszak et al., 2017)

Identification of neurogenic regulators in disease models can serve as key players in restoring healthy physiology in patients with neurodegenerative disorders. Claire Rampon talked about how manipulating mitochondrial properties of new neurons can improve altered cellular properties of an AD mouse brain model and may open new avenues for far-reaching therapeutic strategies for cognitive impairment (Richetin et al., 2017).

Different animal models can have significantly varied neurogenic properties compared to humans which can be particularly useful in developing innovative strategies for human brain repair. Michael Brand talked about how zebrafish is not only an easier model for experimentation, but also provides an excellent source to study adult brain regeneration (Grandel et al., 2006; Kroehne et al., 2011). Brand discussed how zebrafish can be used to study thyroid regulation of adult neurogenesis, emphasising that the genetic factors underlying extensive regeneration in adult zebrafish may be a crucial key to unlock adult brain regeneration in  humans.

Direct reprogramming of adult cells to neurons is an emerging technology which holds great promise for cell-based brain repair. Benedikt Berninger’s lab had identified resident pericytes (a non-neural cell type in the mature brain) to have the potential to be directly converted into neurons (see figure below) (Karow et al., 2012). Berninger talked about the nature of intermediate states taken up by reprogrammed pericytes towards neurogenesis. He showed that as they reprogram, cells pass through a neural stem cell-like state, and that this state is of functional importance for the reprogramming success (Karow et al., 2018-in press). This knowledge may provide new ways for further improving direct reprogramming and in turn, help overcome the scarcity of neurogenesis in the adult mammalian brain.

‘Real-time’ or ‘live’ imaging microscopes allow scientists to observe biological functions of cells and tissues in action. Using an intra-vital imaging procedure, Laure Bally-Cuif showed that her lab was able to dynamically image and track a full population of adult NSCs at a single cell resolution within their niche. This provided the power to deduce live aspects of stem cell behaviour over several weeks in vivo (Dray et al., 2015). Jessberger showed how clonal population derived from neurogenic events can be monitored in vivo using 2-photon microscopy (see figure below) (Pilz et al., 2018). He focused on the importance of using technically straightforward measures to study properties of neurogenesis in its native state.

Fred Gage briefed us about our journey through adult neurogenesis, 2-photon microscopical advances and brain organoids. He showed how human brain organoids can be implanted into mice and observed while it integrates into the rodent CNS (see figure below) (Mansour et al., 2018). The motivation was to find a way to vascularize the human organoid to improve the survival and maturation of these 3-Dimensional human brain tissues to better understand human brain development and study human brain disorders.

Taken together, these talks have emphasised how ground-breaking discoveries coupled with the outstanding development in biomedical technologies has allowed remarkable progress in this field, and provided us with a glimpse into the future and promise of adult neurogenesis.

Conclusion

In light of the recent developments in the field of adult neurogenesis, it is an exhilarating era to exist in. The ‘Adult Neurogenesis 2018’ meeting highlighted many inspiring and pioneering discoveries including insights into neurogenic heterogeneity, control of neurogenesis, and recent technological developments. Neurodegenerative disorders are extremely challenging and expensive to treat. The very discovery of neurogenesis to persist adult mammals including humans has filled us with hope. Given the pace of scientific research, the next few decades might just witness a major leap that humanity can take towards clinical neuroscience.

‘’If I were not in this field today, I would have joined after this conference’’-

Gerd Kempermann

References

Åberg, M.A.I., Pedersen, N.L., Torén, K., Svartengren, M., Bäckstrand, B., Johnsson, T., Cooper-Kuhn, C.M., Åberg, N.D., Nilsson, M., and Kuhn, H.G. (2009). Cardiovascular fitness is associated with cognition in young adulthood. Proc. Natl. Acad. Sci. 106, 20906–20911.

Altman, J., and Das, G.D. (1965). Post-natal origin of microneurones in the rat brain. Nature 207, 953–956.

Artegiani, B., Lindemann, D., and Calegari, F. (2011). Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain. J. Exp. Med. 208, 937–948.

Cajal, S.R. y (1991). Cajal’s Degeneration and Regeneration of the Nervous System (Oxford University Press).

Dray, N., Bedu, S., Vuillemin, N., Alunni, A., Coolen, M., Krecsmarik, M., Supatto, W., Beaurepaire, E., and Bally-Cuif, L. (2015). Large-scale live imaging of adult neural stem cells in their endogenous niche. Development 142, 3592–3600.

Grandel, H., Kaslin, J., Ganz, J., Wenzel, I., and Brand, M. (2006). Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate. Dev. Biol. 295, 263–277.

Karow, M., Sánchez, R., Schichor, C., Masserdotti, G., Ortega, F., Heinrich, C., Gascón, S., Khan, M.A., Lie, D.C., Dellavalle, A., et al. (2012). Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells. Cell Stem Cell 11, 471–476.

Karow, M., Camp, J.G., Falk, S., Gerber, T., Pataskar, A., Gac-Santel, M., Kageyama, J., Brazovskaja, A., Garding, A., Fan, W., et al. (2018). Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program. Nat Neurosci. Jun 18. doi: 10.1038/s41593-018-0168-3. [Epub ahead of print]

Kempermann, G., Gage, F.H., Aigner, L., Song, H., Curtis, M.A., Thuret, S., Kuhn, H.G., Jessberger, S., Frankland, P.W., Cameron, H.A., et al. (2018). Human Adult Neurogenesis: Evidence and Remaining Questions. Cell Stem Cell. April 18. doi: 10.1016/j.stem.2018.04.004. [Epub ahead of print].

Knobloch, M., Braun, S.M.G., Zurkirchen, L., von Schoultz, C., Zamboni, N., Araúzo-Bravo, M.J., Kovacs, W.J., Karalay, O., Suter, U., Machado, R.A.C., et al. (2013). Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230.

Kroehne, V., Freudenreich, D., Hans, S., Kaslin, J., and Brand, M. (2011). Regeneration of the adult zebrafish brain from neurogenic radial glia-type progenitors. Development 138, 4831–4841.

Mansour, A.A., Gonçalves, J.T., Bloyd, C.W., Li, H., Fernandes, S., Quang, D., Johnston, S., Parylak, S.L., Jin, X., and Gage, F.H. (2018). An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441.

Marín-Burgin, A., Mongiat, L.A., Pardi, M.B., and Schinder, A.F. (2012). Unique Processing During a Period of High Excitation/Inhibition Balance in Adult-Born Neurons. Science 335, 1238–1242.

Maruszak, A., Murphy, T., Liu, B., Lucia, C. de, Douiri, A., Nevado, A.J., Teunissen, C.E., Visser, P.J., Price, J., Lovestone, S., et al. (2017). Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease. BioRxiv 175604.

Ming, G., and Song, H. (2011). Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions. Neuron 70, 687–702.

Naylor, A.S., Bull, C., Nilsson, M.K.L., Zhu, C., Björk-Eriksson, T., Eriksson, P.S., Blomgren, K., and Kuhn, H.G. (2008). Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain. Proc. Natl. Acad. Sci. 105, 14632–14637.

Nixon, R.A. (2013). The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997.

Petrik, D., Myoga, M.H., Grade, S., Gerkau, N.J., Pusch, M., Rose, C.R., Grothe, B., and Götz, M. (2018). Epithelial Sodium Channel Regulates Adult Neural Stem Cell Proliferation in a Flow-Dependent Manner. Cell Stem Cell 22, 865-878.e8.

Pilz, G.-A., Bottes, S., Betizeau, M., Jörg, D.J., Carta, S., Simons, B.D., Helmchen, F., and Jessberger, S. (2018). Live imaging of neurogenesis in the adult mouse hippocampus. Science 359, 658–662.

Richetin, K., Moulis, M., Millet, A., Arràzola, M.S., Andraini, T., Hua, J., Davezac, N., Roybon, L., Belenguer, P., Miquel, M.-C., et al. (2017). Amplifying mitochondrial function rescues adult neurogenesis in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 102, 113–124.

Sorrells, S.F., Paredes, M.F., Cebrian-Silla, A., Sandoval, K., Qi, D., Kelley, K.W., James, D., Mayer, S., Chang, J., Auguste, K.I., et al. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381.

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In May we ran a competition to find a meeting reporter for Development’s upcoming meeting on human development and stem cells.

We had some wonderful entries from across the field, and are delighted today to announce the winner: Antonio Barral Gil, a PhD student in Miguel Manzanares’ Lab at CNIC (The Spanish Center for Cardiac Research) in Madrid. Entrants were tasked with writing a short piece on the state of the field, and Antonio’s piece impressed the judges (the Node’s Community Manager Aidan Maartens and Development’s Executive Editor Katherine Brown) for its energy and excitement, as well as its style and content.

Congratulations Antonio!

Antonio obtained his Degree in Biotechnology in 2015 from the Universidad Pablo de Olavide (Sevilla). He then moved to Madrid, where in 2017 he got his Master’s in Molecular Biomedicine at the Universidad Autónoma de Madrid thanks to a CNIC scholarship. He carried out his Master’s thesis in Miguel Manzanares’ lab, focusing on characterizing the role of the transcription factor NANOG during gastrulation. He has recently started his PhD at the same lab, this time focusing on heart regeneration and development. 

The meeting will be held in September; look out for Antonio’s report soon after!

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The López-Schier laboratory at the Helmholtz Zentrum Munich in Germany is seeking creative and highly motivated PhD students or postdoctoral scholars to work within our group of 9 graduate students and postdoctoral fellows. The working language of the laboratory is English.

Our group focuses on understanding the development, regeneration and function of sensory systems. We use the zebrafish as experimental model, and integrate molecular, cellular, behavioural and clinical data. We also have developed new technical approaches to understand organogenesis, including cell-fate acquisition after regeneration from tissue-resident progenitor cells. Mutations in many of the genes that we have identified are responsible for neurological diseases and cancer.

We currently have a fully funded opening for the following projects:

1. Cellular and genetic bases of organogenesis, including cell packing and tissue remodelling. This project combines single-cell transcriptional profiling, genome engineering using CRISPR/Cas9 and quantitative live imaging data by light-sheet microscopy. Preference will be given to candidates with theoretical or practical knowledge in cell biology or biophysics.

2. Control of cell number, organ size and proportions. Using state of the art high-resolution cell tracking, optogenetics, genome engineering and machine learning, we attempt to understand how cells self-organize and to predict cellular behavior during the regenerative response after tissue injury. This project is ideal for a candidate with a background in physics or engineering and a good command of computer programming.

Qualifications & skills

– University studies in biology-related sciences, physics, engineering or computer science (PhD)

– Ideally having recently completed or about to complete a PhD (Postdoctoral)

– Having published or likely to publish at least one first-author paper in a

first/second tier journal (Postdoctoral)

– Candidates for all position should have a strong inner drive, independence, and willingness to work in a highly interdisciplinary team

– A good command of the English language is essential

Laboratory

The team’s projects are interdisciplinary, and are aimed at understanding the basic rules that allow sensory systems to develop, regenerate and function. We use confocal, spinning-disc and light-sheet microscopy imaging, biochemistry, genome engineering by CRISPR/Cas9, laser nanosurgery, optogenetics, and machine learning.

Environment

The Helmholtz Zentrum in an innovative, well-equipped and scientifically stimulating élite research centre located in the outskirts of Munich, one of the most attractive and innovative major cities in Germany. Situated at the foothills of the Alps, Munich is a cosmopolitan city that has ranked among those with the highest quality of life in Europe.

Contact

Please, apply via electronic mail only, including a cover letter with a short statement of research interests and motivation, a Curriculum Vitae including a list of names and email-addresses for two/three academic references, to:

Dr. Hernán López-Schier

Research Unit Sensory Biology & Organogenesis

Helmholtz Zentrum München
Ingolstädter Landstrasse 1
85764 Neuherberg – Munich, Germany

E-mail: hernan.lopez-schier@helmholtz-muenchen.de

Website: http://lopez-schier.strikingly.com

https://www.gsn.uni-muenchen.de/people/faculty/associate/lopez-schier/index.html

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In early June, a group of 30 world-leading experts came together thanks to an invitation by the Company of Biologists to Wiston House (Sussex, UK) to discuss our current understanding about evolutionary and molecular mechanisms that contributed to developing the specific qualities of our human brains.

Fortunately, the Company of Biologists offers fully funded participation for up to ten young career scientists to attend these workshops, and I had the honor to take part in this extraordinary event. The workshop excelled at what many conferences strive for, but only few achieve: open discussion of unpublished data and the big outstanding questions in the field. What I as a youngster appreciated most about the experience was the accepting atmosphere during discussions on- and offline, which was aided by the young participants being offered the same amount of time to present their work in talks as the senior scientists. This even playing field fueled optimism and inspiration for future cross-disciplinary collaborations. This was further facilitated by the workshop bringing together people working on many different aspects of human brain evolution and development: geneticists, to molecular and cellular biologists, behavioralists, anthropologists, mathematicians and engineers.  All were united in the goal of understanding how our brain turned out to be so strikingly different, but also in some aspects so similar, when compared to other mammalian species.

I much appreciated the interspersed discussion sessions led by the three organizers, Arnold Kriegstein, Victor Borrell and Wieland Huttner, which pushed the leading edge of the field to inspire creative thoughts about new directions to take. The participants scratched their heads and engaged in lively discussions concerning some of the big new findings in the field and how to integrate those across scales of investigation from genetics to biophysical models and behavioral outcomes. For instance, we discussed the origin and implications of having a folded cortex with gyri and sulci, their variability and inheritance, whether or not cortical folding is “simply” an epiphenomenon that is only mechanically induced, and what the temporal relationship between folding and connectivity may be. Participants presented interesting data on model systems to approach these questions, including exciting work on brain diseases related to folding and ferrets as a suitable and tractable animal model of a folded brain. Relatedly, when it comes to recent technological advances concerning model systems for human brain development, organoids, three-dimensional cellular networks derived from human ES or induced pluripotent stem cells, are a highly intriguing opportunity that allows for genetic accessibility and experimental control recapitulating many of the early steps of in vivocortical development. It is certainly an exciting time for this technology, which has the potential to fruitfully contribute to our understanding of genetic and cellular events that shape early circuit formation in human neuronal networks.

Throughout the course of the workshop, a lot of emphasis was put on the unique proliferative events that allow for the human brain to accumulate its staggering number of neurons. In the closing discussion session, it was discussed that on top of the sheer number of neurons, it will be important to further our understanding of how different cell types with human-specific molecular signatures contribute to certain traits of the human brain. Relatedly, understanding how synapses and neuronal connectivity may have been shaped differently during human evolution will help our understanding of functional consequences of early developmental events thought to be unique to humans.

Altogether, I am tremendously grateful for having been given the opportunity to attend this workshop and follow the inspiring discussions that certainly broadened my perspective and gave a sense of where the field will move to in the years to come. Wiston House is an amazing place for an event like this, peaceful and remote, in a beautiful landscape that cannot help but inspire creative thinking and groundbreaking new collaborations through thought-sharing. I cannot thank the Company of Biologists, and Wiston House staff enough for providing this unexampled setting to answer unique questions about the mysteries of the past and present existence of our elusive human brains.

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The University of Helsinki is a leading Nordic university with a strong life science research. The Michon research team (http://www.biocenter.helsinki.fi/bi/michon) is located in the Institute of Biotechnology (http://www.biocenter.helsinki.fi/bi/), which is promoting cutting edge research in the biomedical field.
Our team is interested in the epithelial cell behaviour in murine cornea and incisor renewal.

We are currently looking for a postdoctoral researcher

Our future team mate should have
– a PhD in a relevant biomedical discipline with a strong academic track record
– first-author research paper(s) in internationally recognized, peer-reviewed journal(s)
– demonstrated research background in in and ex vivo strategies
– a good experience with mouse handling
– a resourceful attitude and excellent interpersonal skills: capable of contributing to collaborative projects, as well being able to work and plan independently
– critical thinking skills and excellent English communication skills (written, verbal)
– good knowledge of statistics and commitment to rigorous experimental standards

A strong candidate has
– background on epithelial cell biology and developmental biology
– expertise on histology, in situ hybridization, immunostaining
– strong experience with confocal microscopy, image analysis
– a good training on Photoshop and Illustrator

The successful candidate will be proposed an initial 1+1-year contract. However, the candidate will be strongly supported to apply for funding to gain scientific and financial independency. Salary will be commensurate with the credentials and previous experience of the post-doctoral researcher.

The application should be submitted as a single PDF file containing nothing else than
– a cover letter (max 1 page)
– a CV (max 2 pages)
– a statement of previous achievements (max 2 pages)
– a list of publications
– contact information for three referees

Applications should be emailed to frederic.michon@helsinki.fi before the 1st of August. The shortlisted candidates will be interviewed by Skype by mid-August.

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The BSDB’s Autumn Meeting, to be held in Oxford this September, is the third in a series of international workshops on the extraembryonic-embryonic interface, bringing together researchers that address this topic through a wide array of approaches in diverse research organisms. This diversity of approaches is reflected by the organisers – Kat Hadjantonakis, Kristen Panfilio, Tristan Rodriguez, Susana Chuva de Sousa Lopes and Shankar Srinivas.

The workshop style of the meeting allows for extensive discussion and informal interactions.  In addition to short oral presentations from selected abstracts, poster presenters will also have the opportunity to provide two-minute platform introductions to their posters during a dedicated session.  Active, lively participation has been a hallmark of these workshops.

The two previous meetings were in Göttingen in 2015 and Leuven in 2011. To appreciate the breadth of recent advances at the extraembryonic-embryonic interface, check out the meeting report in Development on the previous workshop.

The deadline for early-bird registration, abstract submission, and conference grant applications for current BSDB members is Monday, 16 July

Find out more here:

http://www.bsdbautumn2018.co.uk/home

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A staff research position for an imaging specialist is available in the Parichy lab at University of Virginia. The laboratory focuses on cellular interactions and morphogenetic behaviors, with particular emphasis on post-embryonic neural crest derivatives including pigment cells.

The successful applicant will contribute to on-going studies, will have opportunities to design and pursue new projects, and will oversee microscopy and imaging infrastructure.

The laboratory is equipped with several instruments for high resolution imaging including:

• Zeiss LSM 880 multi-photon laser scanning microscope with Fast Airyscan for super-resolution time-lapse
• Zeiss LSM 800 laser scanning microscope with Airyscan for super-resolution
• Zeiss AxioObserver with Yokogawa spinning disk
• Zeiss AxioObserver for wide-field fluorescence and micro manipulation
• Zeiss AvioZoom v16 with Apotome 2 for structured illumination
• microscopes and stereomicroscopes for routine imaging and analysis

Examples of recent work include:

• macrophage relay for long-distance signaling (in Science)
• long-range signal transduction (in eLife)
• thyroid hormone function in pigment cell lineages (in Science)
• scale pattern formation (preprint)

Applicants should submit the following to Dr. David Parichy (dparichy@virginia.edu):

• CV

• contact information for three references

• brief description of interests, experience and career goals

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The DRSC/TRiP Functional Genomics Resources in the Perrimon group at Harvard Medical School in Boston, MA, USA, is seeking a highly motivated senior-level research technician to join our team. The successful candidate will be responsible for performing molecular biology, cell culture, protein purification, and/or related techniques as part of an overall research program focused on new technology and resource development (e.g. CRISPR technologies, cell-based assays, protein-based studies). The job requires performing independent work that is coordinated with a larger research team. Although most time will be dedicated to hands-on activities, duties will also include quality assessment and data entry.

We provide many opportunities for continued learning in a dynamic work environment. The successful candidate will have access to training on our automated equipment and have the option to attend weekly lab meetings, department seminars, and so on.

You can learn more about our collaborative team, community-focused efforts, and leading-edge research using Drosophila and Drosophila cultured cells at the websites below. Follow the link to the Perrimon lab web page to view details and apply for the job.
https://fgr.hms.harvard.edu/
https://perrimon.med.harvard.edu/

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In our recently published paper¹, we showed that mouse stem cells self-organize into blastocyst-like structures, that we termed blastoids. Because blastoids can be generated in large numbers, can be finely manipulated, and implant in utero, they are a powerful tool to investigate the principles of pre- and post-implantation development. Here is the backstory of our discovery and why we think it is important for science and medicine.

Nature | doi:10.1038/s41586-018-0051-0

The early mammalian embryo, known as the blastocyst, combines the simple and esthetic design of an outer cyst (the future placenta) englobing an inner cell cluster (the future embryo) with the powerful potential to form the whole organism (both embryonic and extra-embryonic). But blastocysts are also few, small, with a small number of cells (<100), and are difficult to physically and genetically manipulate². Many of its operating principles therefore remain unknown.

Stem cell-based embryology.
Stem cells have the intrinsic capacity to self-organize in vitro, as shown with post-implantation models known as gastruloids^3-5 or with organoids. Here, we created the first version of a pre-implantation blastocyst model by promoting the self-organization of mouse embryonic (ESCs) and trophoblast stem cells (TSCs).

The reductionist approach of forming entities ‘from the bottom up’ allows to modulate and reveal previously unnoticed principles of development. In addition, blastoids have technical advantages as compared to blastocysts. Large number of genetically similar structures can be generated, thus opening possibilities for high-throughput screens and for biochemistry-based assays. Also, sub-populations can be rapidly and efficiently fine-tuned. For instance, the trophoblast and embryonic compartments can be physically and genetically modified independently one from another (e.g. dosing/mixing of different genotypes)^{1, 2}.

Altogether, blastoids are models to study the genetically-encoded principles of self-organization, and to generate novel hypotheses on development, which complement the classical ‘top-down’ approach (e.g. observing genetically modified blastocysts). In the future, blastoids, which comprise the cell types necessary to form the whole organism and which can be transferred in utero, might form a full organism solely from stem cells.

Pulling forces to initiate the project.

As an undergraduate in France, I studied a range of physics and engineering-related topics such as polymer physics and fluid dynamics, which are statistical and modelling sciences. However, what grasped my imagination was the experimental concept of tissue engineering as proposed by Linda Griffith and Robert Langer⁶. I applied it during my PhD (2006-2010) by studying the self-organization of pre-vascularized engineered tissues (Prof. Clemens van Blitterswijk, University of Twente, The Netherlands). At the end of it, Clemens van Blitterswijk gave me the freedom to work independently, and to hire two PhD students. A great opportunity to develop new ideas, and at an interesting time: the laboratories of Hans Clevers (Hubrecht Institute) and of Yoshiki Sasai (CDB RIKEN) had just shown that stem cells can form organoids. These discoveries perfectly balanced self-organization and developmental biology.

As I wanted to model the embryo, the blastocyst appeared as a lucid choice in light of the available ESCs and TSCs types. The necessity to gain knowledge on blastocysts stem cells led me to ask Niels Geijsen to become a guest at the Hubrecht Institute for developmental biology and stem cell research (Utrecht, The Netherlands). I obtained an additional grant (“Modulating trophectoderm pluripotency and placental development in artificial blastocysts”, ZonMw project number 116005008), hired two great PhD students Erik Vrij (2011) and Javier Frias Aldeguer (2012), and started pipetting ESCs and TSCs, while finalizing the publication of my PhDs’ papers (2012)^7,8. Erik focused on developing high-content imaging to quantify the phenotypes, while Javier took a deep dive into the relatively unexplored biology of TSCs.

It took us years of intense, stressful and risky work, and we had to run less uncertain projects to maintain a reasonable output, but the team progressively gained expertise and developed efficient, robust experimental pipelines.

How did it come to work?

Self-organization relies on setting up the right boundary conditions to trigger the process. Once initiated, the stem cells remember where they come from, and unleash their intrinsic potential. Two elements were key in creating these initial conditions, which also apply to other self-organizing biological systems. First, a fine control over the confinement of minute, precise number and ratios of ESCs and TSCs. We achieved this using a hydrogel microwell array that I designed and fabricated during my PhD⁸. Second, the possibility to screen for combinations of molecules to trigger the process. We did this by combining transcriptomic databases with the knowledge on signaling pathways previously found by many blastocyst and stem cells labs. The list is long here but we were definitely standing on the shoulders of Janet Rossant, Jennifer Nichols, Austin Smith.

Our approach suggested new mechanisms. For instance, many Wnt ligands are known to be produced by the blastocyst cells (e.g. Wnt7b and Wnt6 by the trophoblasts⁹) but their functions are not known (knock-out mice are not informative¹⁰, possibly due to the plasticity and redundancy of pathways). I clearly remember when stimulating the cells with Wnt activators (Wnt3a, CHIR99021) and looking at the plates 48 hours later. This triggered the cavitation of TSCs, resulting in gorgeous trophectoderm-like cysts. We thought “phenotypically, it is becoming really good and efficient. We might get somewhere, but are we looking at something really occurring in the trophectoderm?” At the moment, no-one knows but blastoids allow to generate such hypotheses that couldn’t be tested until now.

Once the initial conditions are gathered, including a cocktail of six molecules, the stem cells spontaneously organize within 65 hours. The process is rapid and efficient: about 70% of the microwells that include an adequate number of stem cells form a blastoid (see our definition of a blastoid¹).

Making discoveries at the single cell level.

In the meantime, the Hubrecht Institute changed director. Hans Clevers stepped down to focus on national-level activities, and Alexander van Oudenaarden came back from MIT to take the job. He set up a large lab focusing on single cell technologies, which attracted our attention as a powerful way to reveal the gene expression patterns underlying the self-organization of blastoids.

We undertook a series of experiments with Jean-Charles Boisset, postdoc in Alexander’s lab. The initial bulk sequencing run comparing blastoids and blastocysts was probably the second convincing moments that made us feel that we were going in the right direction. With his natural phlegm, Jean-Charles pushed the button on his computer to generate the distance map and simply said “it seems to work”, as a heat-map came out on his screen. The transcriptome of blastoid cells was shifting toward the one of a blastocyst, and we had the green light to depict the phenomena at the single cell level. By physically decoupling the compartments (ESCs or TSCs alone versus blastoid cells) and comparing the single cells with the ones from blastocysts, we pinpointed at changes and at the role of the communication between the TSCs and ESCs.

The ESCs clearly played an inductive role: maintaining trophoblast proliferation, inducing morphogenesis, gate-keeping the progression of trophoblast differentiation, and altogether preserving the potential for the trophectoderm to implant in utero. We established a long list of embryonic inductions that guide trophectoderm development (e.g. metabolic, Jak/STAT, Wnt, SMAD, and Hippo pathways), all of which were interesting mechanisms probably contributing to the formation and implantation of the blastocyst.

Reviewing, forever.

It took us two years to convince the reviewers that the blastoid system was modeling relevant aspects of blastocyst development. We were asked, among many other experiments, to obtain phenotypes upon generation of KO within ESCs and within TSCs. We replaced the ESCs by other cell types to prove the specificity of the embryonic inductions, by the factor that they secrete as well (BMP4, Nodal), and ran high-throughput phenotypic screens to quantify the morphogenetic and functional impact of embryonic inducers.

The in-utero transfer assay was probably crucial to tip the balance as, for the first time, stem cells alone formed a full entity that could be transferred and tested in utero. We did not form a bona fide embryo in utero but blastoids implanted and induced the expression of Aldh3a1 in the deciduae, which is thought to be a specific response to blastocyst implantation (as compared to polymer beads)¹¹. Blastoid cells proliferated, elongated and generated multiple relevant cell types, including giant trophoblasts that hooked up with the mother’s blood system.

Finally, the paper was released in May 2018, and gained attention from the media. I interviewed for the BBC, BBC World News (live!), CNN or Fortune, and more than 100 press articles were released worldwide. We managed to restrain the unfounded fantasy for unethical human reproduction approaches, and to focus on the opportunities to research in the lab the fundamental principles of development or the minor flaws that can occur at the start of pregnancy. These flaws can prevent the conceptus to implant or can contribute to sub-optimal pregnancies (e.g. sub-optimal placenta development) affecting the appearance of chronic diseases during adult life. The biology community also efficiently relayed realistic and positive potential impacts. As free-electrons in stem cell biology and embryology, it has been gratifying to see the positive and encouraging reactions of valued scientists^12-14. A Tweet worth years of research¹⁵.

Imagining the future of blastoids.

Along the way, curiosity led me to discuss with clinicians including human geneticists, epidemiologists, or IVF clinicians. We started to think of realistic possibilities to use blastoids to research in the lab the problems of infertility, contraception, or early pregnancy failure¹². These are extensive societal problems: On one side, humans, which are poorly efficient at procreating, currently delay more and more their pregnancy, which leads to a drop of fertility¹⁶. On the other side, family planning and contraception remains a major global health problem as depicted by WHO¹⁷ and the Bill & Melinda Gates foundation¹⁸.

Overall, women must be able to better plan their pregnancy without decreasing their chance of having a child. Family planning is a huge lever to secure women’s autonomy and well-being, while supporting the health and development of communities. There is a long way in front of us but we are thrilled to see that we might be able to reveal new principles in embryology and, along with clinicians, tackle global health problems.

We are currently recruiting Postdocs and PhD students. Feel free to contact me for more information. www.nicolasrivron.org

[1] Rivron NC [corresponding author], Frias-Aldeguer J, Vrij EJ, Boisset JC, Korving J, Vivié J, Truckenmüller RK, van Oudenaarden A, van Blitterswijk CA †, Geijsen N † [† equal contribution]. Blastocyst-like structures generated solely from stem cells. Nature. 2018. 557, pages106–111 (2018). doi:10.1038/s41586-018-0051-0.

[2] Rivron NC. Formation of blastoids from mouse embryonic and trophoblast stem cells. Protocol Exchange (2018) doi:10.1038/protex.2018.051

[3] van den Brink SC, Baillie-Johnson P, Balayo T, Hadjantonakis AK, Nowotschin S, Turner DA, Martinez Arias A. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development. 2014 Nov;141(22):4231-42. doi: 10.1242/dev.113001.

[4] Harrison SE, Sozen B, Christodoulou N, Kyprianou C, Zernicka-Goetz M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science. 2017 Apr 14;356(6334). pii: eaal1810. doi: 10.1126/science.aal1810.

[5] Warmflash A, Sorre B, Etoc F, Siggia ED, Brivanlou AH. A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat Methods. 2014 Aug;11(8):847-54. doi: 10.1038/nmeth.3016.

[6] http://news.mit.edu/2012/engineering-health-tissue-engineering-growing-organs-1214

[7] Rivron NC, Raiss CC, Liu J, Nandakumar A, Sticht C, Gretz N, Truckenmüller R,  Rouwkema J, van Blitterswijk CA. Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4413-8. doi: 10.1073/pnas.1117627109.

[8] Rivron NC, Vrij EJ, Rouwkema J, Le Gac S, van den Berg A, Truckenmüller RK, van Blitterswijk CA. Tissue deformation spatially modulates VEGF signaling and angiogenesis. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6886-91. doi: 10.1073/pnas.1201626109.

[9] Kemp C, Willems E, Abdo S, Lambiv L, Leyns L. Expression of all Wnt genes and their secreted antagonists during mouse blastocyst and postimplantation development. Dev Dyn. 2005 Jul;233(3):1064-75.

[10] van Amerongen R, Berns A. Knockout mouse models to study Wnt signal transduction. Trends Genet. 2006 Dec;22(12):678-89.

[11] McConaha, M. E., Eckstrum, K., An, J., Steinle, J. J. & Bany, B. M. Microarray assessment of the influence of the conceptus on gene expression in the mouse uterus during decidualization. Reproduction 141, 511–527 (2011).

[12] Rossant J, Tam PPL. Exploring early human embryo development. Science. 2018 Jun 8;360(6393):1075-1076. doi: 10.1126/science.aas9302.

[13] https://f1000.com/prime/733152526#eval793546032

[14] http://www.sciencemediacentre.org/expert-reaction-to-study-reporting-the-development-of-embryo-like-structures-derived-from-mouse-stem-cells/

[15] https://twitter.com/AMartinezArias/status/991729701130563584

[16] https://www.nytimes.com/2018/05/17/us/fertility-rate-decline-united-states.html

[17] http://www.who.int/news-room/fact-sheets/detail/family-planning-contraception

[18] https://www.gatesfoundation.org/What-We-Do/Global-Development/Family-Planning

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This editorial by Aidan Maartens, Andreas Prokop, Katherine Brown and Olivier Pourquié originally appeared in Development

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