Peripheral neuropathies are a common cause of disability and have no cure. The extracellular signals that drive Schwann cell differentiation are important for peripheral nervous system myelination and are potentially accessible to improve failure in certain human peripheral neuropathies. In previous grant cycles, my laboratory identified essential Schwann cell signaling pathways that are modulated by LAMININS in the extracellular matrix. Among them, RAC1, a small-RhoGTPase and YAP and TAZ, effectors of the HIPPO pathway, are essential for normal Schwann cell development. The proposed research will characterize how RAC1 and the HIPPO pathway intersect and identify novel components of these pathways. The novel components include STRIATIN3 and MOB4, members of the STRIPAK complex that we identified as novel RAC1 interactors, and the atypical cadherin CELSR2, a putative mediator of Schwann cell-axon interactions. Preliminary data show that STRIATIN3 and CELSR2 may be important for myelination. Furthermore, this research will identify upstream regulators of the HIPPO pathway in Schwann cells using unbiased approaches. YAP and TAZ may also modulate human neuropathies by mediating mechanical signals and by controlling the expression of genes such as Peripheral Myelin Protein 22 (PMP22), whose altered gene dosage causes 80% of Charcot-Marie-Tooth disease (CMT) cases. To determine if YAP and TAZ modulate PMP22 expression in the context of CMT, YAP and TAZ mutants will be crossed with CMT1 models to determine if PMP22 expression and the consequent phenotypes are modulated. This work will reveal novel fundamental regulators of two important signaling pathways in Schwann cells. As the function of RAC1 and the HIPPO pathway is conserved in different cell types, this work will elucidate novel aspects of cell biology, in addition to myelination, and may reveal ways to modulate signaling pathways relevant in human neuropathies.