SSA - The role of neural specific Src splice variants in neuronal specification and differentiation.

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(N1-Src and N2-Src) is enriched in neural tissue and high levels of N-Src expression are associated with a favourable prognosis in neuroblastoma, leading to spontaneous differentiation and resolution of the cancer. These observations suggest that N-Srcs regulate neuronal differentiation. Our previous work shows that expression of N1-Src drives neuronal differentiation of cells in culture. Furthermore, N-Src isoform expression is highly regulated during Xenopus neuronal development and N-Src knockdown inhibits neuronal differentiation.Objectives: To understand the role that N-Src isoforms play in regulating neuronal specification and differentiation in the developing nervous system and cell culture. This basic research will underpin efforts to understand the potential of N-Srcs as regulators of neuronal differentiation in neuroblastoma and stem cells in culture.Novelty: The normal function of N-Srcs in neuronal differentiation is poorly understood. We bring an exciting combination of expertise to this problem. We have developed reagents that allow us to overexpress and specifically inhibit N-Src activity in the developing embryo and cells in culture. Thus, we are in a uniquelyUNIVERSITY OF YORKDEPARTMENT OF BIOLOGYWhite Rose BBSRC DTP Studentship Bid FormSBForm_WR BBSRC DTP, V2.0 (Sept 2015) Page 2 of 2favourable position to undertake this study.Timeliness: Given that it has recently become apparent that alternative splicing plays a key role in neural development, our proposed study investigating the neural function of Src splice isoforms must be viewed as timely.Experimental Approaches1) We will investigate the effects of manipulating N-Src activity on expression of genes in the conserved Xenopus neurogenic pathway. Having identified key N-Src regulated elements in Xenopus, we will investigate their function in N-Src mediated differentiation of mammalian cells in culture.2) Using N-Src differentiated cells in culture, we will obtain a global view of the N-Src regulated transcriptome. The function of identified targets will then be investigated in the developing embryo and cell.