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.
Peripheral nerve diseases are very common and cause debilitating symptoms that include muscular weakness and atrophy, joint deformities, pain and sensory disturbances. We study the cells that form myelin in peripheral nerves, and showed that they need proteins called laminins, Rac1, Yap and Taz to myelinate. Here we seek to understand how these molecules work during myelination and if they are altered in human peripheral neuropathies, with the goal to promote re-myelination in patients.
|Poitelon, Yannick; Matafora, Vittoria; Silvestri, Nicholas et al. (2018) A dual role for Integrin ?6?4 in modulating hereditary neuropathy with liability to pressure palsies. J Neurochem 145:245-257|
|Ackerman, Sarah D; Luo, Rong; Poitelon, Yannick et al. (2018) GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. J Exp Med 215:941-961|
|Poitelon, Yannick; Feltri, M Laura (2018) The Pseudopod System for Axon-Glia Interactions: Stimulation and Isolation of Schwann Cell Protrusions that Form in Response to Axonal Membranes. Methods Mol Biol 1739:233-253|
|VerPlank, Jordan J S; Lokireddy, Sudarsanareddy; Feltri, M Laura et al. (2018) Impairment of protein degradation and proteasome function in hereditary neuropathies. Glia 66:379-395|
|Ghidinelli, Monica; Poitelon, Yannick; Shin, Yoon Kyoung et al. (2017) Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination. PLoS Biol 15:e2001408|
|Della-Flora Nunes, Gustavo; Mueller, Lauren; Silvestri, Nicholas et al. (2017) Acetyl-CoA production from pyruvate is not necessary for preservation of myelin. Glia 65:1626-1639|
|Sidoli, Mariapaola; Musner, Nicolò; Silvestri, Nicholas et al. (2016) Ablation of Perk in Schwann Cells Improves Myelination in the S63del Charcot-Marie-Tooth 1B Mouse. J Neurosci 36:11350-11361|
|Poitelon, Yannick; Lopez-Anido, Camila; Catignas, Kathleen et al. (2016) YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells. Nat Neurosci 19:879-87|
|Musner, Nicolò; Sidoli, Mariapaola; Zambroni, Desireè et al. (2016) Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy. ASN Neuro 8:|
|Lopez-Anido, Camila; Poitelon, Yannick; Gopinath, Chetna et al. (2016) Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development. Hum Mol Genet 25:3055-3069|
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