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The Journal of Neuroscience, January 25, 2006, 26(4):1179-1189; doi:10.1523/JNEUROSCI.2618-05.2006

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Cellular/Molecular
Peripheral Myelin Protein 22 Is in Complex with 64 Integrin, and Its Absence Alters the Schwann Cell Basal Lamina

Stephanie A. Amici,¹ William A. Dunn, Jr,² Andrew J. Murphy,³ Niels C. Adams,³ Nicholas W. Gale,³ David M. Valenzuela,³ George D. Yancopoulos,³ and Lucia Notterpek^1,2

¹Departments of Neuroscience and ²Anatomy and Cell Biology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0244, and ³Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591

Correspondence should be addressed to Dr. Lucia Notterpek, Department of Neuroscience, McKnight Brain Institute of the University of Florida, 100 Newell Drive, Box 100244, Gainesville, FL 32610-0244. Email: notterp{at}mbi.ufl.edu

Peripheral myelin protein 22 (PMP22) is a tetraspan membrane glycoprotein, the misexpression of which is associated with hereditary demyelinating neuropathies. Myelinating Schwann cells (SCs) produce the highest levels of PMP22, yet the function of the protein in peripheral nerve biology is unresolved. To investigate the potential roles of PMP22, we engineered a novel knock-out (–/–) mouse line by replacing the first two coding exons of pmp22 with the lacZ reporter. PMP22-deficient mice show strong -galactosidase reactivity in peripheral nerves, cartilage, intestines, and lungs, whereas phenotypically they display the characteristics of tomaculous neuropathy. In the absence of PMP22, myelination of peripheral nerves is delayed, and numerous axon–SC profiles show loose basal lamina, suggesting altered interactions of the glial cells with the extracellular matrix. The levels of 4 integrin, a molecule involved in the linkage between SCs and the basal lamina, are severely reduced in nerves of PMP22-deficient mice. During early stages of myelination, PMP22 and 4 integrin are coexpressed at the cell surface and can be coimmunoprecipitated together with laminin and 6 integrin. In agreement, in clone A colonic carcinoma cells, epitope-tagged PMP22 forms a complex with 4 integrin. Together, these data indicate that PMP22 is a binding partner in the integrin/laminin complex and is involved in mediating the interaction of SCs with the extracellular environment.

Key words: basal lamina; integrins; Schwann cells; myelination; neuropathy; laminin

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Received Jun. 24, 2005; revised Dec. 5, 2005; accepted Dec. 5, 2005.

Correspondence should be addressed to Dr. Lucia Notterpek, Department of Neuroscience, McKnight Brain Institute of the University of Florida, 100 Newell Drive, Box 100244, Gainesville, FL 32610-0244. Email: notterp{at}mbi.ufl.edu

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