Regulation of neurogenesis in the cerebellum

小脑神经发生的调节

• 批准号: 6549570
• 负责人: KARINA F MEIRI
• 金额: $ 3.85万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549570
• 关键词: India; apoptosis; biological signal transduction; brain derived neurotrophic factor; cadherins; cell cell interaction; cell cycle; cell differentiation; cell growth regulation; cell proliferation; cerebellum; cooperative study; developmental genetics; developmental neurobiology; fibroblast growth factor; gene expression; gene targeting; genetically modified animals; granule cell; in situ hybridization; laboratory mouse; neural growth associated protein; neurogenesis; neurons; phosphorylation; tissue /cell culture

DESCRIPTION (provided by applicant) A fundamental aspect of developmental neurobiology that we still do not fully understand is how positional information coordinates with local regulation of neurogenetic programs to establish specific patterns in the brain. In vivo, the issue is experimentally accessible in the cerebellum. Inbred mice strains show complex yet invariant patterns of cerebellar foliation that is underpinned by a simple laminar structure comprised of a limited number of defined neuronal subtypes, facilitating characterization of the underlying mechanisms regulating neurogenesis. Examining defects in patterning of cerebellar cortex using mutant mouse models has confirmed that cerebellar patterning is intimately tied to the differentiation program of the neuroblasts, but how regulation occurs is still unclear. Our preliminary results suggest that certain molecules crucial for regulating membrane/cytoskeletal interactions during axon guidance also play important roles in regulating the neurogenic response to patterning information. One of these is the nervous system-specific protein GAP-43. We already know that GAP-43 is required in order for differentiated neurons to respond to signals that give rise to patterning in the CNS. For example, our GAP-43 knockout mouse fails to form either topographic maps in cortex, or telencephalic commissures, because in both cases GAP-43 (-/-) neurons are unable to respond to immunoglobulin superfamily (Ig-SF) mediated axon outgrowth and guidance signals. However the GAP-43 (-/-) mouse also has severe defects in cerebellar patterning that are evident before axonogenesis but during the time that neurogenesis is being regulated by extracellular patterning programs. The objective of this FRICA grant is to understand the molecular mechanisms underlying the disruption of patterning in the cerebellum that occurs when GAP-43 is absent. We describe 3 experiments: First, to determine the earliest stage of cerebellar development that requires GAP-43 function. Second to investigate whether 2 known neurogenic regulators in the cerebellum (bFGF and BDNF) can function when GAP-43 is absent - we already know that bFGF requires GAP-43 and that BDNF can stimulate GAP-43 phosphorylation in growing axons. Finally we will characterize how absence of GAP-43 affects transduction of lg-SF signals that regulate the cell cycle in differentiating cerebellar neurons. This research will be performed primarily in India as an extension on NIH grant# RO1 NS33118.

描述（由申请人提供）我们仍未完全理解的发育神经生物学的一个基本方面是位置信息如何与神经发生程序的局部调节相协调以在大脑中建立特定的模式。在体内，这个问题可以在小脑中进行实验。近交系小鼠品系显示出复杂但不变的小脑叶状结构模式，该模式由简单的层状结构支撑，该结构由有限数量的定义的神经元亚型组成，有助于表征调节神经发生的潜在机制。使用突变小鼠模型检查小脑皮质模式缺陷已证实小脑模式与神经母细胞的分化程序密切相关，但调节如何发生仍不清楚。我们的初步结果表明，在轴突引导过程中调节膜/细胞骨架相互作用至关重要的某些分子也在调节对模式信息的神经源性反应中发挥着重要作用。其中之一是神经系统特异性蛋白 GAP-43。我们已经知道，分化的神经元需要 GAP-43 才能对中枢神经系统中产生模式的信号做出反应。例如，我们的 GAP-43 敲除小鼠无法在皮质或端脑连合中形成地形图，因为在这两种情况下，GAP-43 (-/-) 神经元都无法对免疫球蛋白超家族 (Ig-SF) 介导的轴突生长和引导信号做出反应。然而，GAP-43 (-/-) 小鼠的小脑模式也存在严重缺陷，这些缺陷在轴突发生之前但在神经发生受到细胞外模式程序调节期间很明显。 FRICA 资助的目的是了解 GAP-43 缺失时小脑模式破坏的分子机制。我们描述了 3 个实验：首先，确定需要 GAP-43 功能的小脑发育的最早阶段。其次，研究小脑中 2 个已知的神经源性调节因子（bFGF 和 BDNF）在 GAP-43 缺失时是否可以发挥作用 - 我们已经知道 bFGF 需要 GAP-43，并且 BDNF 可以刺激生长中的轴突中的 GAP-43 磷酸化。最后，我们将描述 GAP-43 的缺失如何影响 lg-SF 信号的转导，从而调节分化小脑神经元的细胞周期。这项研究将主要在印度进行，作为 NIH 拨款 # RO1 NS33118 的延伸。