Molecular Mechanisms of Fate Choice in Neural Stem Cells

描述(由申请人提供)： 该计划的目的是确定在脊椎动物中枢神经系统发育中调节命运选择和亚型指定的分子机制。对命运选择的分子机制的洞察将对神经退行性疾病、脊髓损伤、多发性硬化症和原发性脑癌的治疗具有实际意义。三个假设驱动的项目专注于bHLH转录因子，这些转录因子指导背侧和腹侧神经管的形成。这一具有凝聚力的中心主题受到了一个项目教员的攻击，该教员拥有从计算机科学到发育神经生物学到儿科神经学的各种专业知识。这些项目是互动的，并利用表达载体和生物信息学的核心设施产生的规模经济。在0001子项目中，Michael Greenberg博士和Qiufu Ma博士专注于背神经管，在那里神经原bHLH转录因子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、抑制神经胶质细胞的命运以及神经元亚型的指定。Greenberg和Ma将验证这一假设，即在脑室区域内，NGN作为潜在的转录因子发挥作用，可能还作为转录抑制因子，直到它们被Erk介导的磷酸化短暂激活。在子项目0002中，查尔斯·斯泰尔斯博士和大卫·罗维奇博士将专注于腹侧神经管，其中bHLH转录因子Otl1和Otl2调节形成神经元或少突胶质细胞的命运选择。虽然这两个Olig基因结构相似，表达协调，但它们的生物学功能并不重叠。斯泰尔斯和罗维奇将检验这一假说，即寡核苷酸1和寡核苷酸2的不同生物学功能反映了与转录共激活蛋白的不同相互作用。在子项目0003中，Ma博士和Rowitch博士将带领Greenberg、Siles和其他人对下游转录因子进行全基因组反向遗传筛选，这些转录因子由NGU和Olig基因调节，以控制特定神经元和神经胶质细胞的后期成熟。这一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。这份地图集将通过一个可搜索的网络界面向更广泛的科学界开放。

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.