Regulation of neurogenesis in the cerebellum

小脑神经发生的调节

基本信息

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
项目类别：
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

项目摘要

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）我们仍然不完全了解发育神经生物学的一个基本方面是位置信息如何通过局部调节神经遗传学程序来建立大脑中特定模式的位置信息。在体内，在小脑中可以在实验上解决这个问题。近交小鼠菌株表现出复杂但不变的小脑叶片模式，该模式由一个由有限数量的定义神经元亚型组成的简单层流结构所支撑，从而促进了调节神经发生的基本机制的表征。使用突变小鼠模型检查小脑皮层的缺陷已经证实，小脑模式与神经细胞的分化程序密切相关，但是调节的发生方式仍然不清楚。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在调节对图案信息的神经源反应方面也起着重要作用。其中之一是神经系统特异性蛋白质GAP-43。我们已经知道，需要GAP-43才能使分化神经元响应引起中枢神经系统构图的信号。例如，我们的GAP-43敲除鼠标无法在皮层中形成地形图或尾脑部委员会，因为在这两种情况下，GAP-43（ - / - ）神经元无法对免疫球蛋白超家族（Ig-SF）介导的轴突产生和指导信号做出反应。但是，GAP-43（ - / - ）小鼠在小脑模式中也有严重的缺陷，这些缺陷在轴突发生之前是显而易见的，但是在神经发生受细胞外模式程序调节的过程中。这种frica赠款的目的是了解当缺乏GAP-43时发生的小脑中构图中断的分子机制。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（BFGF和BDNF）中有2个已知的神经源调节剂在不存在GAP-43时是否可以起作用 - 我们已经知道BFGF需要GAP-43，并且BDNF可以刺激GAP-43在生长的轴突中刺激GAP-43磷酸化。最后，我们将表征GAP-43的不存在如何影响LG-SF信号的转导，这些LG-SF信号在分化小脑神经元中调节细胞周期。这项研究将主要在印度进行，以作为NIH Grant＃RO1 NS33118的扩展。