title: MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains.
abstract: Myelinating glial cells exhibit a spectacular cytoarchitecture, because they polarize on multiple axes and domains. How this occurs is essentially unknown. The dystroglycan-dystrophin complex is required for the function of myelin-forming Schwann cells. Similar to other tissues, the dystroglycan complex in Schwann cells localizes with different dystrophin family members in specific domains, thus promoting polarization. We show here that cleavage of dystroglycan by matrix metalloproteinases 2 and 9, an event that is considered pathological in most tissues, is finely and dynamically regulated in normal nerves and modulates dystroglycan complex composition and the size of Schwann cell compartments. In contrast, in nerves of Dy(2j/2j) mice, a model of laminin 211 deficiency, metalloproteinases 2 and 9 are increased, causing excessive dystroglycan cleavage and abnormal compartments. Pharmacological inhibition of cleavage rescues the cytoplasmic defects of Dy(2j/2j) Schwann cells. Thus, regulated cleavage may be a general mechanism to regulate protein complex composition in physiological conditions, whereas unregulated processing is pathogenic and a target for treatment in disease.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
authors.forename: Desirée
authors.initials: D
authors.lastname: Zambroni
authors.forename: Ernesto
authors.initials: E
authors.lastname: Pavoni
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Baragli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Figlia
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.forename: William
authors.initials: W
authors.lastname: Ching
authors.forename: James L
authors.initials: JL
authors.lastname: Salzer
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
mesh_terms: D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000737:chemistry / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000201:enzymology / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D051381:Rats; D012583:Schwann Cells / Q000201:enzymology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000737:chemistry / Q000378:metabolism / Q000473:pathology
chemical_list: D049030:Dystroglycans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9