Cerebellar Granule Cell Lineage and Projection Patterns

描述(申请人提供)：为了了解运动障碍(如小脑性共济失调)如何缺乏正常运动功能所必需的连接，有多种方法对小脑发育进行了表征。使用我们实验室开发的一种新的遗传马赛克系统(称为MADM for Mosic Analysis with Double Marker)，我发现谱系在规定小脑颗粒细胞的轴突投射模式方面发挥了作用。颗粒细胞可以支配浦肯野细胞树突的不同部分，不同地控制局部抑制电路，并影响对许多形式的突触可塑性至关重要的小脑长期抑制。因此，颗粒细胞投射轴突的位置具有重要的功能。我提出了三个目的来研究颗粒细胞轴突投射模式是如何由谱系决定的，并阐明这种谱系特异性的功能意义：(1)对MADM克隆进行系统分析，以进一步表征颗粒细胞谱系和轴突投射模式之间的关系。(2)确定克隆相关的颗粒细胞如何将轴突投射到分子层中的同一层。(3)确定具有不同轴突投射模式的颗粒细胞是否接受不同类别苔藓纤维的输入。

DESCRIPTION (provided by applicant): Various methods have characterized cerebellar development in order to understand how connections necessary for normal motor function may be deficient in movement disorders, such as cerebellar ataxia. Using a novel genetic mosaic system that we have developed in our laboratory (termed MADM for Mosaic Analysis with Double Markers), I found that lineage plays a role in specifying the axonal projection pattern of cerebellar granule cells. Granule cells can innervate different parts of the Purkinje cell dendrite, differentially control local inhibitory circuits, and affect cerebellar long-term depression critical for many forms of synaptic plasticity. Thus, where granule cells project their axons is of functional importance. I propose three aims to investigate how granule cell axonal projection patterns are specified by lineage and to elucidate the functional implication of this lineage specificity: (1) Systematic analysis of MADM clones to further characterize the relationship between granule cell lineage and axonal projection patterns. (2) Determine how clonally related granule cells project axons to the same lamina in the molecular layer. (3) Determine whether granule cells with different axonal projection patterns receive input from distinct classes of mossy fibers.