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 ?61 and ?71 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.

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Peripheral nerve diseases cause 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 integrins to myelinate. Here we seek to understand how integrins are needed, why myelination fails in patients when integrins are defective, and how to promote re-myelination in patients with neuropathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-R (02))
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Morris, Jill A
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State University of New York at Buffalo
Schools of Medicine
United States
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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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