MECHANISMS OF REGULATING ASTROGLIAL LINEAGE DEVELOPMENT

描述：使用表皮生长因子(EGF)来源的胚胎 脑室下区(SVZ)多潜能神经前体细胞，我们有 确定了转化生长因子b(TGFb)的一个亚类 超家族，骨形态发生蛋白(BMPs)，介导 星形胶质细胞的选择性、剂量依赖的精细加工，同时 抑制神经元和少突胶质细胞谱系的发育。 骨形态发生蛋白配体和骨形态发生蛋白I、II受体的转录本和蛋白质 亚基存在于脑和SVZ祖细胞中，在适当的 来调节这些营养作用的时间。与激活 LIFb受体、BMPs和bFGF促进放射状胶质细胞的早期表达， 星形胶质细胞的后期增强(BMP)或抑制(BFGF) 表型。这些观察表明，BMP代表了一个新的阶层 可能调节星形胶质细胞谱系承诺的信号分子和 可能与不同的早期信号分子相互作用。这位将军 这一提议背后的假设是，BMP是具有指导性的信号 它调节星形胶质细胞谱系承诺和BMP调节 受体亚单位和/或BMP配体决定星形胶质细胞的模式 大脑发育过程中的谱系细化：A.克隆和单细胞 分析将被用于确定BMP是否促进星形胶质细胞 无论是不同的BMP，效应都构成了指导性的细胞信号 抑制神经元和少突胶质细胞谱系及其祖细胞 体外细胞对BMP的反应性与BMP的变化相关 受体表达。B.分离的EGF反应性祖细胞和组织 来自胶质形成的连续阶段的切片将被检查以确定 BMP-祖细胞反应性程度的变化， 星形胶质细胞谱系的种类和时空表达的变化 BMP受体和配体的相互关系以建立体内外相关性。C。 激光诱导因子和碱性成纤维细胞生长因子在调控骨形态发生蛋白表达中的作用 将研究放射状神经胶质细胞群体的细胞反应性 确定这些细胞变化是否反映了对BMP的相反影响 受体表达。这些研究将进一步加深我们对 表观遗传信号和调控细胞发育的细胞机制 星形胶质血统。因为许多细胞过程都存在 在星形胶质细胞发育过程中可能会在病理过程中重现 这些发现也可能对我们的 了解神经胶质细胞在创伤、脱髓鞘中的反应 疾病与哺乳动物中枢神经系统的细胞转化。

DESCRIPTION: Using epidermal growth factor (EGF)-derived embryonic subventricular zone (SVZ) multipotent neural progenitor cells, we have identified a subclass of the transforming growth factor b (TGFb) superfamily, the bone morphogenetic proteins (BMPs), that mediate the selective, dose-dependent elaboration of astrocytes, with concurrent suppression of neuronal and oligodendroglial lineage development. Transcripts and proteins for the BMP ligands and BMP type I and II receptor subunits are present in brain and SVZ progenitor cells at the appropriate times to mediate these trophic actions. In concert with activation of the LIFb receptor, BMPs and bFGF potentiate the early expression of radial glia, with later enhancement (BMP) or inhibition (bFGF) of the astroglial phenotype. These observations suggest that the BMPs represent a new class of signaling molecules that may regulate astroglial lineage commitment and may interact with distinct early signaling molecules. The general hypothesis underlying this proposal is that the BMPs are instructive signals that regulate astroglial lineage commitment, and that regulation of BMP receptor subunits and/or BMP ligands determine the pattern of astrocyte lineage elaboration during brain development: A. Clonal and single cell analysis will be utilized to determine whether the BMP astroglial-promoting effects constitute instructive cellular signals, whether different BMPs suppress the neuronal and oligodendroglial lineages and whether progenitor cell responsiveness to the BMPs in vitro correlates with changes in BMP receptor expression. B. Isolated EGF-responsive progenitor cells and tissue sections from sequential stages of gliogenesis will be examined to define changes in the degree of BMP-progenitor cell responsiveness, the profile of astroglial lineage species, and alterations in the spatiotemporal expression of BMP receptors and ligands to establish in vitro-in vivo correlations. C. The role of LIF and bFGF in modulating the BMP-mediated expression and cellular responsiveness of radial glial populations will be studied to determine whether these cellular changes reflect opposing effects on BMP receptor expression. These studies will further our understanding of the epigenetic signals and cellular mechanisms that regulate the development of the astroglial lineage. Because many of the cellular processes present during astroglial development may be recapitulated during pathological states, these findings may also have important implications for our understanding of glial-mediated responses in traumatic injury, demyelinating disorders and mammalian central nervous system cellular transformation.