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 #
2R01NS045630-10A1
Application #
8629249
Study Section
Special Emphasis Panel (ZRG1-MDCN-R (02))
Program Officer
Morris, Jill A
Project Start
2003-07-01
Project End
2019-01-31
Budget Start
2014-02-15
Budget End
2015-01-31
Support Year
10
Fiscal Year
2014
Total Cost
$346,484
Indirect Cost
$127,734
Name
State University of New York at Buffalo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Porrello, Emanuela; Rivellini, Cristina; Dina, Giorgia et al. (2014) Jab1 regulates Schwann cell proliferation and axonal sorting through p27. J Exp Med 211:29-43
D'Antonio, Maurizio; Musner, Nicolo; Scapin, Cristina et al. (2013) Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice. J Exp Med 210:821-38
Pellegatta, Marta; De Arcangelis, Adele; D'Urso, Alessandra et al. (2013) *6*1 and *7*1 integrins are required in Schwann cells to sort axons. J Neurosci 33:17995-8007
Colom, Bartomeu; Poitelon, Yannick; Huang, Wenlong et al. (2012) Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves. FASEB J 26:1064-76
Berti, Caterina; Bartesaghi, Luca; Ghidinelli, Monica et al. (2011) Non-redundant function of dystroglycan and ýý1 integrins in radial sorting of axons. Development 138:4025-37
La Marca, Rosa; Cerri, Federica; Horiuchi, Keisuke et al. (2011) TACE (ADAM17) inhibits Schwann cell myelination. Nat Neurosci 14:857-65
Court, Felipe A; Zambroni, Desirée; Pavoni, Ernesto et al. (2011) MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains. J Neurosci 31:12208-17
Fratta, Pietro; Saveri, Paola; Zambroni, Desiree et al. (2011) P0S63del impedes the arrival of wild-type P0 glycoprotein to myelin in CMT1B mice. Hum Mol Genet 20:2081-90
Jin, Fuzi; Dong, Baoxia; Georgiou, John et al. (2011) N-WASp is required for Schwann cell cytoskeletal dynamics, normal myelin gene expression and peripheral nerve myelination. Development 138:1329-37
Jung, Junyang; Cai, Wenting; Lee, Hyun Kyoung et al. (2011) Actin polymerization is essential for myelin sheath fragmentation during Wallerian degeneration. J Neurosci 31:2009-15

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