Molecular Mechanisms of Fate Choice in Neural Stem Cells

描述（由申请人提供）： 该项目的目的是确定在发育中的脊椎动物中枢神经系统中调节命运选择和亚型特化的分子机制。深入了解命运选择的分子机制将对神经退行性疾病、脊髓损伤、多发性硬化和原发性脑癌的治疗具有实际意义。三个假设驱动的项目集中在bHLH转录因子，直接形成的背侧和腹侧神经管。这个有凝聚力的中心主题是由一个专业知识，从计算机科学，通过发育神经生物学到儿科神经学的程序教师攻击。这些项目是互动的，利用表达载体和生物信息学核心设施产生的规模经济。在子项目0001中，Michael Greenberg和Qiufu Ma博士重点研究了背侧神经管，其中前神经bHLH转录因子的Ngn亚家族调节神经发育的多个方面，包括细胞周期退出的时间，细胞迁移，神经元连接，胶质细胞命运的抑制以及神经元亚型身份的规范。Greenberg和Ma将检验这一假设，即在心室区，Ngns作为潜在的转录因子发挥作用，并且可能作为转录的阻遏物，直到它们被ERK介导的磷酸化瞬时激活。在子项目0002中，Charles Stiles和大卫罗维奇博士将重点研究腹侧神经管，在腹侧神经管中，bHLH转录因子Olig1和Olig2调节命运选择以形成神经元或少突胶质细胞。虽然两个Olig基因结构相似且协同表达，但其生物学功能不重叠。Stiles和Rowich将检验Olig1和Olig2的不同生物学功能反映了与转录辅激活蛋白的差异相互作用的假设。在子项目0003中，马博士和罗维奇博士将带领格林伯格、斯泰尔斯和其他人通过全基因组反向遗传筛选，寻找由Ngu和Olig基因调控的下游转录因子，以控制专门神经元和神经胶质细胞的后期成熟。这个筛选的一个副产品将是发育中的神经管中转录因子表达的全基因组图谱。该地图集将通过一个可搜索的网络界面向更广泛的科学界提供。

DESCRIPTION (provided by applicant): The objective of this program is to define the molecular mechanisms that regulate fate choice and subtype specification in the developing vertebrate central nervous system. Insights into the molecular mechanisms of fate choice will have practical overtones for therapy of neurodegenerative diseases, spinal cord injury, multiple sclerosis and primary cancers of the brain. Three hypothesis-driven projects focus on bHLH transcription factors that direct formation of the dorsal and the ventral neural tube. This cohesive central theme is attacked by a program faculty with expertise that ranges from computer science, through developmental neurobiology to pediatric neurology. The projects are interactive and exploit economies of scale generated by core facilities for expression vectors and bioinformatics. In Subproject 0001, Drs. Michael Greenberg and Qiufu Ma focus upon the dorsal neural tube where the Ngn subfamily of proneural bHLH transcription factors regulate multiple aspects of neural development, including the timing of cell cycle exit, cell migration, neuronal connectivity, suppression of the glial cell fate, and the specification of neuronal subtype identity. Greenberg and Ma will test the hypothesis that, within the ventricular zone, Ngns function as latent transcription factors, and perhaps as repressors of transcription, until they are transiently activated by Erk-mediated phosphorylation. In Subproject 0002, Drs. Charles Stiles and David Rowitch will focus upon ventral neural tube where the bHLH transcription factors Olig1 and Olig2 regulate the fate choice to form neurons or oligodendrocytes. Though structurally similar and coordinately expressed, the two Olig genes have non-overlapping biological functions. Stiles and Rowitch will test the hypothesis that the distinct biological functions of Olig1 and Olig2 reflect differential interactions with transcription co-activator proteins. In Subproject 0003, Drs. Ma and Rowitch will lead Greenberg, Stiles and others through a genome wide reverse genetic screen for downstream transcription factors that are regulated by Ngu and Olig genes to control later maturation of specialized neurons and glia. One byproduct of this screen will be a genome wide map of transcription factor expression in developing neural tube. This atlas will be made accessible to the broader scientific community via a searchable web-based interface.