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在CNS中指定成体干细胞龛（SCN）的细胞和分子机制，该CNS在整个生命过程中含有干细胞。SCN位于室管膜下前区，在此处，源自成体干细胞的新生神经元通过吻侧迁移流（RMS）迁移至嗅球（OB）并分化为中间神经元。成体SCN由排列在新纹状体心室表面的星形胶质细胞和室管膜细胞组成。这两种细胞类型都来源于外侧神经节隆起（LGE）中的胚胎SCN。一系列转录因子已被证明在发育中的LGE的不同结构域内调节细胞命运。我们已经确定了一个叉头转录因子（FOXJ 1），我们显示是在一个子集的胚胎祖细胞中的LGE的表达，并表现出持久的表达在出生后SCN。我们提出的研究将揭示SCN分化的新机制，以及它们在调节成体干细胞和出生后大脑神经发生中的共同作用。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适当发育对于正常CNS发育和功能是必不可少的。我们的研究正在解开的作用，放射状胶质细胞的一个子集，在发展中的LGE可能会引起一个子集的层特异性神经元的嗅球。虽然一些研究集中在大脑皮质放射状胶质细胞的神经元后代的规格，介导的室管膜细胞和星形胶质细胞的子集，建立成人SCN的规格的分子机制是完全未探索的。对这些机制的全面理解是非常有意义的，因为它们在成体干细胞和/或出生后SCN中的操纵可以允许产生新的神经元和产生引导神经元迁移到受损或患病的脑区域，以及潜在的纠正重大出生缺陷如脑积水。 公共卫生相关性：我们提出的研究将确定一个基因的新的调控机制，该基因驱动出生后和成人神经干细胞的细胞生态位的发展。在出生后和成人大脑中，区域特异性神经发生的持续调节机制的描述对于成人神经干细胞在基于细胞的治疗中的未来应用至关重要。

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. PUBLIC HEALTH RELEVANCE: Our proposed studies will determine novel regulatory mechanisms of a gene that drives the development of a cellular niche for postnatal and adult neural stem cells. Delineation of mechanisms that regulate persistence of regionally specific neurogenesis in the postnatal and adult brain is critical to future application of adult neural stem cells in cell-based therapies.