Characterization of Rac1 effectors in myelination.

描述（由申请人提供）：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导致先天性肌营养不良症，包括多种周围神经系统异常。层粘连蛋白和层粘连蛋白受体也影响细胞骨架和RhoGTPAse分子突变在沙克-玛丽-图斯神经症。层粘连蛋白信号传导受损导致雪旺细胞轴突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-基质相互作用诱导细胞极化的复杂例子。在之前的两期研究中，我们发现轴突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α6ß1和α7ß1整合素和Rac1 RhoGTPase，而随后的大直径轴突脱离前髓鞘雪万细胞需要层粘连蛋白受体糖代谢障碍。我们现在提出解决三个基本的细胞生物学问题和阻碍我们理解分选和髓鞘形成的障碍：雪旺细胞基表面的层粘连蛋白和整合素如何促进与相反表面（靠近轴突的尖状表面）轴突的相互作用？层粘连蛋白的信号如何与轴突神经调节蛋白的信号相结合？髓鞘胶质的接触和包裹轴突是如何开始的，机械动力和先进的？通过利用我们所产生的小鼠突变体和试剂的显著收集，我们现在处于独特的位置来解决这些问题，并确定髓鞘形成中的新介质。这些研究将解决对立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有关，但对径向分选和髓鞘形成的开始也很重要；在一些人类神经病变和其他髓磷脂疾病中受损。

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.