The insulin receptor regulates axon guidance

描述（由申请人提供）：胰岛素受体在无脊椎动物和脊椎动物的中枢神经系统中大量表达，尽管它们的作用仍然难以捉摸。我们发现果蝇胰岛素受体（DInr）在视觉系统轴突引导中的新功能。我们已经证明，在发育过程中，光感受器细胞（R细胞）轴突从视网膜靶向到大脑形成精确的视网膜定位图，DInr功能是必要的。DInr作为Dock通路的引导受体：DInr直接与Dock相互作用，通过激活下游效应因子p21活化激酶将细胞外信号与轴突迁移联系起来。DInr的这种功能在遗传上独立于果蝇IRS同源基因Chico。我们的研究结果表明，胰岛素受体家族在整个动物王国的轴突指导中起着普遍的作用。在这个应用中，我们提出实验来进一步阐明DInr在调节轴突引导中的确切作用。我们将对R细胞中与DInr功能丧失相关的异常进行详细的表型表征。此外，我们将确定DInr和Dock（一种进化上保守的SH2/SH3结构域适配器蛋白）之间相互作用的分子基础。这些研究将使我们能够区分DInr通过Dock途径调节轴突引导和细胞生长的机制，这被认为是由chico依赖途径介导的。最后，我们将启动体外和体内研究，以确定DInr调节轴突引导的配体。受体可能对环境中一个或多个配体提供的吸引或排斥信号作出反应，将R细胞靶向到发育中的大脑中的正确地形位置。我们的研究将对理解胰岛素受体在大脑中的功能以及阐明神经元胰岛素受体控制饮食行为、学习和记忆的机制具有广泛的意义。

DESCRIPTION (provided by applicant): Insulin receptors are abundantly expressed in the central nervous system of invertebrates and vertebrates, although their roles have remained elusive. We have discovered a novel function for the Drosophila insulin receptor (DInr) in axon guidance in the visual system. We have shown that DInr function is necessary for photoreceptor cell (R cell) axon targeting from the retina to the brain to form a precise retinotopic map during development. DInr functions as a guidance receptor for the Dock pathway: DInr interacts directly with Dock, to link extracellular signals to axonal migration via activation of the downstream effector p21-activated kinase. This function of DInr is genetically independent of Chico, the Drosophila IRS homolog. Our findings suggest a general role for the insulin receptor family in axon guidance throughout the animal kingdom. In this application, we propose experiments to further elucidate the precise role of DInr in regulating axon guidance. We will carry out a detailed phenotypic characterization of abnormalities associated with loss of DInr function in R cells. Further, we will define the molecular basis for the interaction between DInr and Dock, an evolutionarily conserved SH2/SH3 domain adapter protein. These studies will allow us to distinguish the mechanisms utilized by DInr to regulate axon guidance through the Dock pathway and cell growth, thought to be mediated by a Chico-dependent pathway. Finally, we will initiate in vitro and in vivo studies to identify the ligand for DInr in regulating axon guidance. The receptor may respond to either attractive or repellent cues provided in the environment by one or more ligands to target R cells to their correct topographic locations in the developing brain. Our studies will have broad implications for understanding the function of insulin receptors in the brain and for elucidating mechanisms underlying neuronal insulin receptor control of eating behavior, learning and memory.