title: Jab1 regulates Schwann cell proliferation and axonal sorting through p27.
abstract: Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211- and, possibly, neuregulin 1 (Nrg1)-derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain-binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies.
authors.affiliation: Institute of Experimental Neurology (INSPE), Division of Neuroscience; 2 Department of Neurology; and 3 Division of Immunology, Transplantation, and Infectious Disease; San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Porrello
authors.forename: Cristina
authors.initials: C
authors.lastname: Rivellini
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dina
authors.forename: Daniela
authors.initials: D
authors.lastname: Triolo
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: Daniela
authors.initials: D
authors.lastname: Ungaro
authors.forename: Martina
authors.initials: M
authors.lastname: Panattoni
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.forename: Ruggero
authors.initials: R
authors.lastname: Pardi
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Stefano Carlo
authors.initials: SC
authors.lastname: Previtali
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D015153:Blotting, Western; D001837:Body Weights and Measures; D001973:Bromodeoxyuridine; D000075686:COP9 Signalosome Complex; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test; D012583:Schwann Cells / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex; D001973:Bromodeoxyuridine