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

描述（由申请人提供）：正常哺乳动物脑发育涉及祖细胞的调节生长及其分化为特化细胞类型。胚胎发育过程中祖细胞功能的异常可导致干细胞群的不适当扩增和异常神经胶质成熟，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（NF 1）是最常见的遗传性疾病之一，其中受影响的儿童发展神经胶质细胞瘤（视神经胶质瘤）。使用NF 1作为模型系统来研究神经干/祖细胞（NSC）在体外和体内的功能，我们已经表明胚胎NSC中NF 1蛋白（神经纤维蛋白）功能的丧失导致（1）增加的NSC增殖和自我更新以及（2）增加的胶质细胞谱系扩增。基于我们的实验观察，我们假设，neurofibromin是需要在体内NSC的维护和神经胶质细胞的成熟。在这个建议中，我们设计了补充的体外和体内实验，以确定神经纤维蛋白如何控制神经干细胞的维持和神经胶质细胞分化。本提案的总体目标是采用实验室产生的基因工程Nf 1突变小鼠和Nf 1缺陷的神经干细胞作为易处理的实验平台，以确定关键的控制机制，管理神经干细胞功能的发展中的中枢神经系统。 公共卫生相关性：儿童发生脑肿瘤的最常见遗传性疾病是1型神经纤维瘤病（NF 1）。该建议采用NF 1作为实验模型系统，以了解神经干细胞在与脑肿瘤形成相关的小鼠正常脑发育中的作用。这些研究可能会导致开发专门针对导致儿童脑肿瘤的关键生长和命运控制途径的疗法。

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.