Molecular regulation of neurogenesis and cell fate

描述（由申请人提供）：本提案的总体目标是阐明控制脊椎动物中枢神经系统（CNS）中神经元产生的分子机制。成年脊椎动物的CNS由大量功能不同的神经元类型组成，这些神经元类型占据脑和脊髓内的特定和可重复的位置。在整个发育的CNS中，单个神经元以精确的空间和时间顺序从增殖的前体产生。这个顺序的正确执行涉及严格控制从分裂多能前体到具有不同表型特征的新生神经元的过渡。尽管这一转变在神经发生中至关重要，但目前尚不清楚涉及多少步骤以及它们是否或如何联系在一起。脊髓代表了一个理想的模型系统，在其中检查控制CNS中神经元类型的分化和多样化的分子机制。在脊髓的神经发生过程中，研究表明，Prox 1的表达仅限于有丝分裂后，前迁移位于脑室下区（SVZ）的中间神经元前体，但特别是从运动神经元生成域排除。后来，在妊娠中期，Prox 1在不同的神经元和神经胶质谱系中表达。许多其他因子的表达，包括作为有丝分裂后神经决定因子的那些因子，与SVZ细胞中的Prox 1重叠。这些发现表明，Prox 1是一个遗传程序的一部分，对正常的神经发生很重要，它的功能是确定脊髓中不同神经元群体的独特特征。为了验证这一点，将使用体外和体外方法来确定Prox 1和相关因子对神经发生的贡献。这些研究将为控制脊椎动物脊髓神经元的发生和分化的分子机制提供重要的见解，这一主题与治疗CNS损伤和退行性疾病的人类患者的治疗方法的发展直接相关。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the molecular mechanisms that control the production of neurons in the vertebrate central nervous system (CNS). The CNS of adult vertebrates is composed of a vast number of functionally distinct neuronal types that occupy specific and reproducible positions within the brain and spinal cord. Throughout the developing CNS, individual neurons are generated from proliferative precursors in a precise spatial and temporal order. The correct implementation of this order involves tight control over the transition from dividing multipotent precursors to newborn neurons with distinct phenotypic characteristics. Despite the central importance of this transition in neurogenesis, it is currently unclear how many steps are involved and whether or how they are linked. The spinal cord represents an ideal model system in which to examine the molecular mechanisms controlling the differentiation and diversification of neuronal types in the CNS. During neurogenesis in the spinal cord, studies show that Prox1 expression is restricted exclusively to post-mitotic, pre-migratory interneuron precursors located within a sub-ventricular zone (SVZ), but is specifically excluded from the motoneuron-generating domain. Later, at mid-gestation, Prox 1 is expressed in diverse neuronal and glial lineages. The expression of a number of other factors, including those that function as post-mitotic neural determinants, overlap with Prox1 in SVZ cells. These findings suggest that Prox1 is part of a genetic program that is important for normal neurogenesis, and that it functions to determine the unique characteristics of distinct neuronal populations in the spinal cord. To test this, both in-vitro and in-vitro approaches will be used to define the contribution of Prox1 and related factors to neurogenesis. These studies will provide important insights into the molecular mechanisms that control the genesis and differentiation of neurons in the vertebrate spinal cord, a subject with direct relevance to the development of therapeutic approaches for treating human patients with CNS injuries and degenerative disorders.