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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045630-14
Application #
9415106
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Morris, Jill A
Project Start
2003-07-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
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
Feltri, M Laura; Poitelon, Yannick; Previtali, Stefano Carlo (2016) How Schwann Cells Sort Axons: New Concepts. Neuroscientist 22:252-65
Yin, Xinghua; Kiryu-Seo, Sumiko; Kidd, Grahame J et al. (2015) Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin. Glia 63:66-77
Petersen, Sarah C; Luo, Rong; Liebscher, Ines et al. (2015) The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron 85:755-69
Poitelon, Y; Bogni, S; Matafora, V et al. (2015) Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination. Nat Commun 6:8303

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