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

N1-Src和N2-Src在神经组织中富集，高水平的N-Src表达与神经母细胞瘤的良好预后相关，导致癌症的自发分化和消退。这些观察结果表明，N-Srcs调节神经元分化。我们以前的工作表明，N1-Src的表达驱动培养细胞的神经元分化。此外，N-Src亚型表达高度调节爪蟾神经元发育和N-Src敲低抑制neuronal differentiation.Objectives：了解的作用，N-Src亚型发挥调节神经元的规格和分化，在发展中的神经系统和细胞培养。这项基础研究将支持努力了解的潜力，N-Srcs作为调节神经母细胞瘤和干细胞在culture.新奇神经分化的正常功能的N-Srcs了解甚少。我们为这个问题带来了令人兴奋的专业知识组合。我们已经开发出试剂，使我们能够在发育中的胚胎和培养细胞中过表达和特异性抑制N-Src活性。因此，我们在一个重要的纽约大学生物系白玫瑰BBSRC DTP学生投标表格SBForm_WR BBSRC DTP，V2.0（2015年9月）第2页，共2页，是开展本研究的有利条件。时间：鉴于最近已经很明显，选择性剪接在神经发育中起着关键作用，我们提出的研究Src剪接异构体的神经功能的研究必须被视为及时的。实验方法1）我们将研究操纵N-Src活性对非洲爪蟾保守神经源性通路基因表达的影响。在非洲爪蟾中鉴定了关键的N-Src调控元件后，我们将研究它们在N-Src介导的哺乳动物细胞分化中的功能。2）使用培养的N-Src分化细胞，我们将获得N-Src调控转录组的全局视图。然后将在发育中的胚胎和细胞中研究所鉴定的靶标的功能。

(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.