Mechanisms Regulating Astroglial Lineage Development

超出所提供的空间。 在哺乳动物大脑皮层发育过程中，神经干细胞（NSC）产生连续的神经干细胞分化波。 神经元和神经胶质。我们已经证明，骨形态发生蛋白（BMP）促进特定的谱系决定 这取决于神经干细胞的发育阶段。在早期胚胎脑室区（VZ），BMP最初 增强细胞死亡，但随后促进神经元谱系定型和随后的细胞成熟， 积极抑制放射状胶质细胞和少突胶质细胞的生成。相反，在胚胎晚期， 在室管膜下区（SVZ），BMPs增强星形胶质细胞的发育，现在积极抑制这种发育。 神经元和少突胶质细胞。分化抑制因子（ID）家族成员调节神经原性 碱性螺旋环螺旋（bHLH）转录因子，ID 1和3抑制神经发生，同时 维持国家安全委员会的命运我们发现在胚胎神经发生和胶质细胞发生过程中， 上调NSC中ID 2和ID 4的转录物，并促进靶祖物种中的ID核易位。 我们假设BMP介导的细胞和谱系效应涉及ID 2和ID 4，因为抑制ID 2和/或ID 4， ID 4表达阻止了这些BMP认可的对VZ和SVZ NSC的积极和消极发育作用， 对ID 2-/-、ID 4-/-和ID 2-/-ID 4-/-小鼠的初步分析显示， 与用ID 1-/-、ID 3-/-和ID 1-/-ID 3-/-小鼠观察到的那些不同。这一建议的基本假设是：1。 BMP还通过促进神经干细胞分化的特定途径协调皮质发育事件 作为替代谱系命运的主动抑制，2. BMP还调节初始VZ NSC库的大小， 神经元成熟的进行性阶段，3. ID 2和ID 4通过以下途径差异介导这些不同的过程： ID 2和ID 4在皮质发育中的作用将被研究 通过定义过表达或消除ID 2和/或ID 4对NSC谱系定型的影响， 对BMP的反应通过分析ID 2-/-、ID 4-/-和ID 4-/-中的神经发育，将在体内检查它们的作用。 ID 2-/-ID 4-/-突变小鼠。这些研究将进一步加深我们对控制 胚胎大脑皮质神经发生和胶质细胞发生过程中神经谱系发育的变化。

EXCEED THE SPACE PROVIDED. During mammalian cerebral cortical development, neural stem cells (NSCs) give rise to successive waves of neurons and glia. We have shown that the bone morphogenetic proteins (BMPs) promote specific lineage decisions that depend on the developmental stage of NSCs. Within the early embryonic ventricular zone (VZ), BMPs initially enhance cell death but later promote neuronal lineage commitment and subsequent cellular maturation and also actively suppress the generation of radial glia and oligodendrocytes. By contrast, within the late embryonic subventricular zone (SVZ), BMPs potentiatethe elaborationof astrocytesand nowactively suppress the elaboration of neurons and also oligodendrocytes. Members of the inhibitor of differentiation(ID) family regulate neurogenic basic-helix-loop-helix (bHLH) transcription factors, and ID1 and 3 inhibit neurogenesis while simultaneously preserving the NSC fate. We have found that during both embryonic neurogenesis and gliogenesis, BMPs upregulate transcripts for ID2 and ID4 in NSCs and promote ID nuclear translocation in target progenitor species. We hypothesizethat BMP-mediated cellular and lineage effects involve ID2and ID4 because inhibition of ID2 and/or ID4 expression prevents these BMP-sanctioned positive and negative developmental effects on VZ and SVZ NSCs, and preliminary analysis of ID2-/-, ID4-/- and ID2-/-ID4-/- mice has revealed defects in neural development distinct from those seen with ID1-/-, ID3-/- and ID1-/-ID3-/-mice. The basic hypotheses underlying this proposal are: 1. BMPs orchestrate cortical developmental events by promotion of specific pathways of NSC differentiation as well as active suppression of alternate lineage fates, 2. BMPs also modulate the size of the initial VZ NSC pool and progressive stages of neuronal maturation, 3. ID2 and ID4 differentially mediate these diverse processes through changing roles within distinct progenitor species.The role of ID2 and ID4 in cortical development will be examined in vitro by defining the effects of overexpressingor ablating ID2 and/or ID4 on NSC lineage commitment and responses to the BMPs. Their roles will be examined in vivo by analyzing neural development in ID2-/-, ID4-/- and ID2-/-ID4-/-mutant mice. These studies will further our understandingof the molecular mechanisms governing the changing profiles of neural lineage elaboration during embryonic cerebralcortical neurogenesis and gliogenesis.