Characterization of Rac1 effectors in myelination.

描述(申请人提供)：层粘连蛋白是许多组织发育的基础。层粘连蛋白和相关基因的突变会导致先天性肌营养不良，包括多个周围神经系统异常。层粘连蛋白和层粘连蛋白受体也影响细胞骨架和在Charcot-Marie-Tooth神经病中突变的RhoGTPAse分子。层粘连蛋白信号受损导致雪旺细胞对轴突进行径向分选的发育步骤停止。径向分选是髓鞘形成的先决条件，也是细胞-细胞和细胞-基质相互作用如何合作诱导细胞极化的复杂例子。在前两个授权期，我们证明了轴突的分选是一个多步骤的过程，轴突识别、分离和包裹的早期步骤需要层粘连蛋白受体α6？1和α7？1整合素和Rac1 RhoGTP酶，而随后的大口径轴突的分离需要层粘连蛋白受体营养不良多糖。我们现在提出解决三个基本的细胞生物学问题和我们理解分选和髓鞘形成的障碍：雪旺细胞基面的层粘连蛋白和整合素如何促进与相反表面(顶状表面，靠近轴突)的轴突的相互作用？层粘连蛋白的信号是如何与轴突神经调节蛋白的信号整合的？通过髓鞘胶质细胞接触和包裹轴突是如何启动的、机械驱动的和高级的？通过利用我们产生的大量小鼠突变体和试剂，我们现在处于独特的地位，可以解决这些问题，并在髓鞘形成过程中识别新的介体。这些研究将解决相反极化表面之间的关键功能关系，这与任何极化细胞的生物学相关，但对径向分选和髓鞘形成的启动也很重要；在几种人类神经疾病和其他髓鞘疾病中受到损害。

DESCRIPTION (provided by applicant): Laminins are fundamental for development of many tissues. Mutations in laminins and related genes cause Congenital Muscular Dystrophies that include multiple peripheral nervous system abnormalities. Laminins and laminin receptors also affect cytoskeletal and RhoGTPAse molecules mutated in Charcot-Marie-Tooth neuropathies. Impaired laminin signaling causes arrest in the developmental step of radial sorting of axons by Schwann cells. Radial sorting is a prerequisite for myelination and a sophisticated example of how cell-cell and cell-matrix interactions cooperate to induce cellular polarization. In the two previous grant periods we showed that axonal sorting is a multistep process, and that the early steps of axonal recognition, segregation and wrapping require the laminin receptors α6ß1 and α7ß1 integrins and Rac1 RhoGTPase, whereas the subsequent detachment of large caliber axons by pro-myelinating Schwann cells requires the laminin receptor dystroglycan. We now propose to address three fundamental cell biological questions and roadblocks to our understanding of sorting and myelination: how do laminins and integrins, at the basal surface of Schwann cells, promote interaction with axons that occurs at the opposite surface (apical-like surface, near axons)? How are signals from laminins integrated with signals from axonal neuregulins? How are contact and wrapping of axons by myelinating glia initiated, mechanically powered and advanced? By capitalizing on the remarkable collection of mouse mutants and reagents that we have generated, we are now in the unique position to address these issues and to identify novel mediators in myelination. These studies will address the critical functional relationship between opposing polarized surfaces, which is relevant to the biology of any polarized cell, but is also important for radial sorting and the initiation of myelination; and is impaired in several human neuropathies and other myelin diseases.