α6β1 and α7β1 Integrins Are Required in Schwann Cells to Sort Axons

Abstract

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 ␤1 integrin subunit are required for radial sorting; however, which of the 11 ␣ integrins that can pair with ␤1 forms the functional receptor is unknown. Here we conditionally deleted all the ␣ subunits that form predominant laminin-binding ␤1 integrins in Schwann cells and show that only ␣6␤1 and ␣7␤1 integrins are required and that ␣7␤1 compensates for the absence of ␣6␤1 during development. The absence of either ␣7␤1 or ␣6␤1 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 ␣6/␣7 integrin mutants show only a subset of the abnormalities found in mutants lacking all ␤1 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, ␣6␤1 and ␣7␤1 are the laminin-binding integrins required for axonal sorting, but other Schwann cell ␤1 integrins, possibly those that do not bind laminins, may also contribute to radial sorting during peripheral nerve development.

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

“…Further exploration of focal adhesion genes that encode proteins linking Schwann cells to the extracellular matrix identified several laminins and their integrin receptors. Schwann cell myelination requires the integration of laminin activities for process extension and morphogenesis (58 -63 (64,65). All of these genes have Sox10-bound enhancers (see Lamb1 and Itga6 in Fig.…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…Laminin, integrin and FAK provide essential cues for axonal sorting and myelination in vivo (Feltri et al, 2002;Chen and Strickland, 2003;Grove et al, 2007;Berti et al, 2011;Pellegatta et al, 2013). Thus, GPR126 and integrins provide links to the extracellular matrix and signal in a matrix-dependent manner to control axonal sorting and myelination.…”

The Polarity Protein Pals1 Regulates Radial Sorting of Axons

“…Although some of the factors that control myelination have been described (Michailov et al, 2004;Taveggia et al, 2005), the mechanisms regulating many other Schwann cell functions remain poorly understood. For example, how Schwann cells sort axons, initiate myelination, execute the dramatic cytoskeletal rearrangements necessary for axon wrapping and myelin extension, and form distinct subcellular membrane domains remains poorly understood.…”

“…Recently, insights into the mechanisms of myelination have come from viewing it as yet another example of cellular polarization (Salzer, 2003;Masaki, 2012;Simons et al, 2012). In epithelial cells, a well-characterized model of polarity, three main complexes regulate polarization and junction formation: (1) the Par complex, consisting of Par3, Par6, and atypical protein kinase C (aPKC), provides the signaling complex that regulates formation of the apical domain.…”