NEUROFIBROMIN REGULATION OF NEURAL STEM CELL FUNCTION IN VITRO AND IN VIVO

描述（由申请人提供）：正常哺乳动物大脑发育涉及祖细胞的调节生长及其向特化细胞类型的分化。胚胎发生过程中祖细胞功能的异常可导致干细胞群的不适当扩张和神经胶质的异常成熟，并可能导致许多脑异常，包括儿童脑肿瘤的形成。1型神经纤维瘤病（NF1）是最常见的遗传性疾病之一，其影响的儿童发展为神经胶质细胞肿瘤（视神经胶质瘤）。利用NF1作为模型系统在体外和体内研究神经干/祖细胞（NSC）的功能，我们发现NF1蛋白（神经纤维蛋白）在胚胎NSCs中的功能缺失会导致(1)NSC增殖和自我更新增加，(2)胶质谱系扩增增加。根据我们的实验观察，我们假设神经纤维蛋白是维持NSC和神经胶质细胞成熟所必需的。在这个提议中，我们设计了互补的体外和体内实验来确定神经纤维蛋白如何控制NSC维持和胶质细胞分化。本提案的总体目标是采用实验室生成的基因工程Nf1突变小鼠和Nf1缺陷的NSCs作为可处理的实验平台，以确定在发育中的中枢神经系统中控制NSC功能的关键控制机制。

DESCRIPTION (provided by applicant): Normal mammalian brain development involves the regulated growth of progenitor cells and their differentiation into specialized cell types. Abnormalities in progenitor cell function during embryogenesis can lead to inappropriate expansion of stem cell populations and abnormal glial maturation, and potentially result in a number of brain abnormalities, including the formation of brain tumors in children. Neurofibromatosis type 1 (NF1) is one of the most common genetic conditions in which affected children develop glial cell tumors (optic pathway gliomas). Using NF1 as a model system to study neural stem/progenitor cell (NSC) function in vitro and in vivo, we have shown that loss of Nf1 protein (neurofibromin) function in embryonic NSCs results in (1) increased NSC proliferation and self-renewal and (2) increased glial lineage expansion. Based on our experimental observations, we hypothesize that neurofibromin is required for NSC maintenance and glial cell maturation in vivo. In this proposal, we have designed complementary in vitro and in vivo experiments to determine how neurofibromin controls NSC maintenance and glial cell differentiation. The overall objective of this proposal is to employ laboratory-generated genetically-engineered Nf1 mutant mice and Nf1-deficient NSCs as tractable experimental platforms to define the critical control mechanisms that govern NSC function in the developing central nervous system. PUBLIC HEALTH RELEVANCE: The most common genetic condition in which children develop brain tumors is neurofibromatosis type 1 (NF1). This proposal employs NF1 as an experimental model system to understand the role of neural stem cells in normal brain development in mice relevant to brain tumor formation. These studies may lead to the development of therapies that specifically target the critical growth and fate control pathways that cause brain tumors in children.