A systems biology approach to neural crest development: The role of noise in fate choice from bipotent precursors.

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Noise originates in many aspects of the biology of gene expression and accounts for much of the variability that we see in all biological systems. The robustness of such systems, with discrete cell-types stably differentiated, indicates that the architecture of genetic components has evolved to minimize the impact of noise. Counter-intuitively, however, theory predicts that cells may also use dynamical noise to help drive fate specification and commitment processes i.e. understanding noise may be vital to understanding these cellular processes. Thus we propose a study to account for the effects of noise on the Waddington landscape of embryonic development. We will employ an iterative cycle of experimental genetics and quantitative mathematical modelling within a systems biology framework to begin to test this hypothesis in vivo. Our model system, zebrafish pigment cell differentiation, is ideal since this process is genetically well-characterised, easily manipulable, and shares many characteristics with mammals. We will investigate two pigment cell-types, black melanocytes and shiny iridophores, descending from a common progenitor cell, building directly on our recent breakthroughs in modelling the gene regulatory network (GRN) of melanocyte differentiation and in identifying key genetic mechanisms active in the common progenitor. We will identify the topology of the GRN of the common pigment cell progenitor. We will construct in an iterative manner both deterministic and stochastic models of this GRN, using key experimental data obtained in vivo to aid parameter fitting. Mathematical analysis will then allow us to assess the effects of intrinsic and extrinsic noise. This new approach will be widely applicable to understanding fate choice in other stem cell and developmental systems. The detailed understanding we will generate has important implications for lifelong health as the destabilisation of differentiation is strongly linked to aging and cancer.

This research will contribute directly to the BBSRC's priority areas, including in the short term forming a pioneering in vivo exemplar of the BBSRC's priority areas Systems approach to biological research 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 are likely to contribute to Aging research and Economic and social impact. Finally, by developing quantitative models of differentiation, we expect to contribute to the priority of 3Rs in research using animals.

Due to its fundamental nature, this research is unlikely in the short term to have major direct benefits to human health or to the UK economy. However, it will be important for developing new techniques for systems biology of vertebrates, for developing in silico models of a medically-important cell-type, the melanocyte, and for understanding a highly medically-relevant process, fate choice in multipotent stem cells. The broader importance of our research lies principally in its interdisciplinary nature, exploring capabilities and limitations of in silico modelling in development. Thus, the most immediate impact will be via transfer of knowledge to other researchers. The most direct beneficiaries will be academic researchers in the zebrafish development and genetics, pigment cell biology, mathematical biology, biological physics and systems biology fields. 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 gene function in pigment cell development, phenotypic information, much expanded gene regulatory networks (GRNs), methodological advances regarding GRN development and testing and the use of dynamical systems and stochastic processes in development, as well as 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.

Policy-makers, including National Centre for 3Rs Research, will benefit in the longer term from developing improved methods for modelling in vivo GRNs; as these models become more sophisticated and quantitative, this will in time help to reduce the numbers of animals used in research.

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. Our contribution will be indirect, by showing the value of the interdisciplinary approach we are pioneering, and also direct, towards understanding healthy melanocyte function. 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.

Within the public sector, and for the public themselves, our work will contribute to the public understanding of science, especially since pigment cell biology is so 'visual', and thus of interest to organisations such as the Bath Royal Literary and Scientific Institution. 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 could be of considerable interest to the public.

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