Cerebellar Granule Cell Lineage and Projection Patterns

描述（由申请人提供）：为了了解正常运动功能所需的连接如何在运动障碍（如小脑共济失调）中缺乏，各种方法表征了小脑的发育。使用我们在实验室开发的一种新型遗传镶嵌系统（称为MADM，即双标记镶嵌分析），我发现谱系在指定小脑颗粒细胞轴突投影模式中起作用。颗粒细胞可以支配浦肯野细胞树突的不同部位，不同地控制局部抑制回路，并影响小脑长期抑制，这对多种形式的突触可塑性至关重要。因此，颗粒细胞轴突投射的位置具有重要的功能。我提出了三个目标来研究颗粒细胞轴突投射模式是如何被谱系指定的，并阐明这种谱系特异性的功能含义：(1)系统分析MADM克隆，进一步表征颗粒细胞谱系和轴突投射模式之间的关系。(2)确定克隆相关颗粒细胞如何将轴突投射到分子层的同一层上。(3)确定具有不同轴突投射模式的颗粒细胞是否接受来自不同种类苔藓纤维的输入。

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.