Rethinking the neural crest - a novel dynamic hypothesis of neural crest fate restriction

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Despite decades of modern research, a fundamental question remains unresolved: how does a fully multipotent neural crest (stem) cell generate each of the diverse derivatives? Since the end of the last century the neural crest field has been divided into two intellectual camps, one favouring a Direct Fate Restriction mechanism, the other a Progressive Fate Restriction mechanism. Based on an unexpected finding in our analysis of single cell expression profiles, we propose a new, Cyclical Fate Restriction hypothesis, which resolves the conflict and reconciles the two viewpoints. We suggest that intermediate progenitors are more multipotent than previously thought, but also highly dynamic in vivo. Hence, highly multipotent progenitor states exist in a quasi-stable state, but cycling through a 'cloud' of transient cell states biased towards different fates. As a result, snapshot examination of marker expression reveals heterogeneity, while lineage labeling may show high diversity of fates within large cell clones. Our focus in this project is on testing this revolutionary view of neural crest development by using an interdisciplinary approach. Mathematical modelling has been influential in understanding stem cell development, but theory currently neglects Direct and Cyclical Fate Restriction models. Using diverse experimental and modelling approaches, we will develop a comprehensive picture of neural crest cell heterogeneity in vivo, establish a detailed mathematical framework based on Dynamic Systems Theory for interpreting this heterogeneity in the light of all models, and quantitate key fate specification signals experienced by neural crest cells. We will also re-examine the key experimental data underpinning the Progressive Fate Restriction model. Together, these studies will test our revolutionary new hypothesis of this key stem cell, with implications for stem cell biology and its applications reaching well-beyond the basic biology studied here.

This research will contribute directly to the BBSRC's priority areas, including the strategic priority areas of Data driven biology, Systems approaches to the biosciences and Technology development for bioscience. In the medium to long-term, potential healthcare benefits (including improved diagnosis/personalised treatment) resulting from better understanding of basic biological processes will contribute to Healthy ageing across the lifecourse priority. We note also our continued international collaboration with Dr V. Makeev (Vavilov Institute of General Genetics, Moscow), extending our Royal Society-funded collaboration (ends Feb 2019), so that we also contribute to International Partnerships.

Academic impact
Due to its fundamental nature, the major direct benefits to human health or to the UK economy are longer term. In the shorter term this research will be important to develop new techniques for systems biology of vertebrates, by building in silico developmental models to understand a highly medically-relevant process, fate choice in multipotent stem cells. Our work's broader importance lies principally in its interdisciplinary nature, exploring new mathematical modelling approaches in stem cell development. Thus, the most immediate impact will be via transfer of knowledge to other researchers. The most direct beneficiaries will be academic researchers in development, stem cell biology, pigment cell biology, mathematical biology, biological physics and systems biology.

Economic and societal impact
Researchers in the commercial private sector, including research charities (e.g. CRUK) and the pharmaceuticals/regenerative medicine communities (e.g. Pfizer) will benefit from better understanding of stem cell biology, both in general and in pigment cell development, through methodological advances in modelling of fate specification processes and through secondary use of our data. This will have impact far beyond the immediate biological significance of our research. By reaching these groups of academic and biotechnology researchers, we will influence the quality of life of the UK public, by providing basic research informing our understanding of ageing and disease, and allowing safe and effective use of stem cells.

In the commercial private sector, the data and models generated will be important to the pharmaceutical industry and research charities working on pigmentation disorders and melanoma and other neurocristopathies. Our contribution will be indirect, by showing the value of the interdisciplinary approach we are pioneering, and also direct, towards understanding healthy pigment cell function and their stem cell origins (important, for example, since melanoma development is often viewed, in part, as a dedifferentiation of melanocytes to a more proliferative stem cell-like state). This research is vital to our better understanding of abnormal function and to the development of therapies against diseases such as melanoma and Waardenburg syndrome, so that patients will also be beneficiaries in the longer term.

Within the public sector, and for the public themselves, our work will contribute to the public understanding of science. Pigment cell biology is so 'visual', and thus of interest to organisations such as the Bath Royal Literary and Scientific Institution. At Surrey we will engage with secondary schools and colleges to promote the progression of students on to higher education. Our work could be used to explain the concepts of systems and mathematical biology, and differentiation in health and disease. Because of the relevance to melanoma, this topic is of considerable interest to the public.

This project will have high impact on PDRAs and RA Training, in its combination and integration of innovative techniques in experimental in vivo biology and mathematical modelling, who will obtain a superb training in this increasingly attractive area, making them highly employable in academe or industry.