Transcriptional regulation of aging in the adult neural stem cell niche

描述(申请人提供)：这项建议的目标是阐明在中枢神经系统中终生容纳干细胞的成体干细胞生态位(SCN)的细胞和分子机制。SCN位于前脑室下区，成体干细胞来源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。成体SCN由星形胶质细胞和室管膜细胞组成，排列在新纹状体的脑室表面。这两种细胞类型均来源于外侧神经节隆起(LGE)内的胚胎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。我们已经确定了一个叉头转录因子(FOXJ1)，我们发现它在LGE中的一部分胚胎祖细胞中表达，并在出生后的SCN中持续表达。我们提出的研究将阐明SCN分化的新机制，以及它们在成体干细胞和出生后脑内神经发生调节中的伴随作用。现在公认的是，放射状胶质细胞及其星形细胞后代的发育时机和适当的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子集在LGE发育中的作用，这可能会在嗅球中产生一种特定层神经元的子集。虽然许多研究已经集中在大脑皮层放射状胶质细胞的神经元后代的指定上，但调节室管膜细胞和建立成年SCN的星形胶质细胞亚群的分子机制完全没有被探索。全面了解这些机制是非常有意义的，因为它们在成体干细胞和/或出生后SCN中的操作可能允许产生新的神经元，并引导神经元迁移到受损或患病的脑区，并有可能纠正主要的出生缺陷，如脑积水。 公共卫生相关性：我们提议的研究将确定一种基因的新调节机制，该基因驱动出生后和成年神经干细胞的细胞生态位的发展。描述调节出生后和成人大脑中局部特异性神经发生的持续的机制对于成人神经干细胞未来在基于细胞的治疗中的应用至关重要。

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.