Compensatory Mechanisms Regulating Neuronal Fate Following Notch Signaling Perturbation

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The process by which a sheet of undifferentiated cells within a developing embryo gives rise to a fully operational brain remains a pressing scientific problem with significant implications for understanding how brains function. Each neuron in the developing brain must adopt an appropriate cellular identity through a precise genetic program of spatial and temporal gene expression. Although these genetic programs do not always play out in an accurate manner, embryonic tissues have an enhanced ability to recover from perturbations as compared to adult tissues. The overall goal of this research is to identify the molecular mechanisms by which the embryonic nervous system responds to and recovers from these deviations from normal development. The experiments will employ a well-suited animal model system, namely the amphibian Xenopus laevis, that displays not only remarkable ability to compensate following genetic perturbation of the developmentally important Notch signaling pathway, but also employs a similar suite of genes to those regulating early human neural development. Using molecular, cellular and genetic tools, this research will uncover the specific genes and pathways that allow tissues to recover from genetic perturbation of Notch signaling. This will broaden our understanding of the ways in which the highly conserved Notch signaling pathway function to promote proper development of the nervous system in animals.Broader Impacts: This knowledge will contribute to understanding how and why processes go awry in human brain development and how these genetic pathways can potentially be manipulated in the emerging field of regenerative medicine. Equally importantly, the research will entail extensive undergraduate involvement in a manner that blends teaching and research; a cadre of undergraduate students, working with the principal investigator, will conduct the research as part of their science education and the experiments will also be incorporated into a new research-based genomics course. In order to engage the broader community, local teachers will have the opportunity to participate in the research through summer workshops.