Transcriptional regulation of aging in the adult neural stem cell niche

描述（由申请人提供）：本提案的目标是阐明中枢神经系统中成体干细胞生态位（SCN）的细胞和分子机制，这些机制在整个生命过程中都是干细胞的避风港。SCN位于前脑室下区，成体干细胞衍生的新生神经元通过吻侧迁移流（RMS）迁移到嗅球（OB）并分化为中间神经元。成年SCN由星形细胞和室管膜细胞组成，排列在新纹状体的心室表面。这两种细胞类型都来源于外侧神经节突起（LGE）的胚胎SCN。一系列转录因子已被证明在发育中的LGE的不同区域内调节细胞命运。我们发现叉头转录因子（FOXJ1）在LGE的一个胚胎祖细胞亚群中表达，并在出生后SCN中持续表达。我们提出的研究将揭示SCN分化的新机制，以及它们在成年干细胞和出生后大脑神经发生的调节中的伴随作用。现在已经确定，放射状胶质细胞及其星形胶质细胞后代的发育时机和发育对中枢神经系统的正常发育和功能至关重要。我们的研究正在揭示放射状胶质细胞在LGE发育过程中的作用，这可能会导致嗅球中特定层神经元的形成。虽然许多研究都集中在大脑皮层中放射状胶质细胞的神经元后代的特化上，但介导室管膜细胞和星形胶质细胞亚群的特化的分子机制却完全没有被探索。对这些机制的全面理解是非常有趣的，因为它们在成体干细胞和/或出生后SCN中的操作可能允许产生新的神经元和引导神经元迁移到受损或患病的大脑区域，并可能纠正主要的出生缺陷，如脑积水。

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate cellular and molecular mechanisms that specify the adult stem cell niche (SCN) in the CNS that harbors stem cells throughout life. The SCN is situated in the anterior subventricular zone where newly born neurons derived from adult stem cells migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) and differentiate into interneurons. The adult SCN consists of astrocytes and ependymal cells that line the ventricular surface of the neostriatum. Both these cell types are derived from an embryonic SCN in the lateral ganglion eminences (LGE). A constellation of transcription factors have been shown to regulate cell fate within distinct domains of the developing LGE. We have identified a fork head transcription factor (FOXJ1) which we show is expressed in a subset of embryonic progenitors in the LGE, and exhibits persistent expression in the postnatal SCN. Our proposed studies will shed light on novel mechanisms underlying differentiation of the SCN, and their concomitant role in regulation of adult stem cells and neurogenesis in the postnatal brain. It is now well established that the timing and proper development of radial glia and their astrocytic progeny are essential for normal CNS development and function. Our studies are unraveling the role of a subset of radial glial cells in the developing LGE which may give rise to a subset of layer specific neurons in the olfactory bulb. While a number of studies have focused on specification of neuronal progeny of radial glial cells in the cerebral cortices, molecular mechanisms that mediate the specification of ependymal cells and a subset of astrocytes that establish the adult SCN are completely unexplored. A comprehensive understanding of these mechanisms is of great interest as their manipulation in adult stem cells and/or the postnatal SCN may allow for production of new neurons and generation of guided neuronal migration to damaged or diseased brain regions, and potential correction of major birth defects such as hydrocephalus.