α6β1 and α7β1 integrins are required in Schwann cells to sort axons.
During development, Schwann cells extend lamellipodia-like processes to segregate large- and small-caliber axons during the process of radial sorting. Radial sorting is a prerequisite for myelination and is arrested in human neuropathies because of laminin deficiency. Experiments in mice using targeted mutagenesis have confirmed that laminins 211, 411, and receptors containing the β1 integrin subunit are required for radial sorting; however, which of the 11 α integrins that can pair with β1 forms the functional receptor is unknown. Here we conditionally deleted all the α subunits that form predominant laminin-binding β1 integrins in Schwann cells and show that only α6β1 and α7β1 integrins are required and that α7β1 compensates for the absence of α6β1 during development. The absence of either α7β1 or α6β1 integrin impairs the ability of Schwann cells to spread and to bind laminin 211 or 411, potentially explaining the failure to extend cytoplasmic processes around axons to sort them. However, double α6/α7 integrin mutants show only a subset of the abnormalities found in mutants lacking all β1 integrins, and a milder phenotype. Double-mutant Schwann cells can properly activate all the major signaling pathways associated with radial sorting and show normal Schwann cell proliferation and survival. Thus, α6β1 and α7β1 are the laminin-binding integrins required for axonal sorting, but other Schwann cell β1 integrins, possibly those that do not bind laminins, may also contribute to radial sorting during peripheral nerve development.
San Raffaele Scientific Institute, Milano 20132, Italy, Hunter James Kelly Research Institute, University at Buffalo, State University of New York, New York 14203, Development and Stem Cells Program, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch 67404, France, Department of Medicine, Children's Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom, and Robert Wood Johnson Medical School, Piscataway, New Jersey, New Jersey 08854.
Marta
M
Pellegatta
Adèle
A
De Arcangelis
Alessandra
A
D'Urso
Alessandro
A
Nodari
Desirée
D
Zambroni
Monica
M
Ghidinelli
Vittoria
V
Matafora
Courtney
C
Williamson
Elisabeth
E
Georges-Labouesse
Jordan
J
Kreidberg
Ulrike
U
Mayer
Karen K
KK
McKee
Peter D
PD
Yurchenco
Angelo
A
Quattrini
Lawrence
L
Wrabetz
Maria Laura
ML
Feltri
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D039121:Integrin alpha6beta1 / Q000502:physiology*; D016023:Integrins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure
D039121:Integrin alpha6beta1; D016023:Integrins; C082908:integrin alpha7beta1