MECHANISMS OF REGULATING ASTROGLIAL LINEAGE DEVELOPMENT

描述：使用表皮生长因子（EGF）衍生的胚胎 室管膜下区（SVZ）多能神经祖细胞，我们有 鉴定了转化生长因子B（TGF B）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、剂量依赖性加工，同时 抑制神经元和少突胶质细胞谱系发育。 BMP配体和BMP I型和II型受体的转录物和蛋白质 亚基存在于脑和SVZ祖细胞中， 时间来调节这些营养作用。 与激活的 LIFb受体、BMPs和bFGF增强放射状胶质细胞的早期表达， 随后增强（BMP）或抑制（bFGF）星形胶质细胞 表型。 这些观察结果表明，BMP代表了一个新的类别， 可能调节星形胶质细胞谱系定型的信号分子， 可能与不同的早期信号分子相互作用。 总 这一建议的基础假设是，骨形态发生蛋白是指导性信号 其调节星形胶质细胞谱系定型，以及BMP调节 受体亚单位和/或BMP配体决定星形胶质细胞的模式 脑发育过程中的谱系加工：A.克隆和单细胞 分析将用于确定BMP星形胶质细胞促进 影响构成指导性的细胞信号，无论不同的BMP 抑制神经元和少突胶质细胞谱系， 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应答祖细胞和组织 将检查胶质细胞生成的连续阶段的切片，以确定 BMP-祖细胞反应性程度的变化， 星形胶质细胞谱系物种，以及时空表达的改变 的BMP受体和配体，以建立体外-体内相关性。 C. LIF和bFGF在调节BMP介导的表达中的作用， 放射状神经胶质细胞群的细胞反应性将被研究， 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 表观遗传信号和调节发育的细胞机制 星形胶质细胞谱系 因为许多细胞过程 在星形胶质细胞的发展过程中， 这些发现也可能对我们的研究产生重要影响。 理解创伤性损伤、脱髓鞘、 疾病和哺乳动物中枢神经系统细胞转化。

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.