The insulin receptor regulates axon guidance

描述(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。我们发现了果蝇胰岛素受体(DInr)在视觉系统轴突引导中的一种新功能。我们已经证明了DInr功能对于光感受器细胞(R细胞)轴突从视网膜到大脑的靶向在发育过程中形成精确的视网膜定位图是必要的。DInr是Dock途径的引导受体：DInr直接与Dock相互作用，通过激活下游效应器p21激活的激酶，将细胞外信号与轴突迁移联系起来。DInr的这一功能在遗传上独立于果蝇IRS同源基因CHICO。我们的发现表明，胰岛素受体家族在整个动物界的轴突指导中起着普遍的作用。在这一应用中，我们建议进行实验，以进一步阐明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，我们将定义DInr和Dock之间相互作用的分子基础，Dock是一种进化上保守的SH2/SH3结构域适配蛋白。这些研究将使我们能够区分DInr通过Dock途径和细胞生长调节轴突引导的机制，人们认为DInr是由ChICO依赖的途径介导的。最后，我们将启动体外和体内研究，以确定DInr在调节轴突引导方面的配体。受体可以对环境中一个或多个配体提供的吸引或排斥的提示做出反应，以将R细胞定位于它们在发育中的大脑中的正确地形图位置。我们的研究将对了解大脑中胰岛素受体的功能以及阐明神经元胰岛素受体控制进食行为、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.