Non-redundant function of dystroglycan and β1 integrins in radial sorting of axons

Abstract

SUMMARYRadial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during peripheral nerve development. Radial sorting is impaired in models of human diseases, congenital muscular dystrophy (MDC) 1A, MDC1D and Fukuyama, owing to loss-of-function mutations in the genes coding for laminin 2, Large or fukutin glycosyltransferases, respectively. It is not clear which receptor(s) are activated by laminin 211, or glycosylated by Large and fukutin during sorting. Candidates are 1 integrins, because their absence phenocopies laminin and glycosyltransferase deficiency, but the topography of the phenotypes is different and 1 integrins are not substrates for Large and fukutin. By contrast, deletion of the Large and fukutin substrate dystroglycan does not result in radial sorting defects. Here, we show that absence of dystroglycan in a specific genetic background causes sorting defects with topography identical to that of laminin 211 mutants, and recapitulating the MDC1A, MDC1D and Fukuyama phenotypes. By epistasis studies in mice lacking one or both receptors in SCs, we show that only absence of 1 integrins impairs proliferation and survival, and arrests radial sorting at early stages, that 1 integrins and dystroglycan activate different pathways, and that the absence of both molecules is synergistic. Thus, the function of dystroglycan and 1 integrins is not redundant, but is sequential. These data identify dystroglycan as a functional laminin 211 receptor during axonal sorting and the key substrate relevant to the pathogenesis of glycosyltransferase congenital muscular dystrophies.

Role of Integrin-Linked Kinase in Multi-drug Resistance of Human Gastric Carcinoma SGC7901/DDP Cells

“…Of great interest was how ILK modulated these molecules. It has been shown that the expression of ERCC1 (Li et al, 2012) and GST-π (Zhang et al, 2009) is regulated by MAPK/ ERK pathway, and the RhoE has a direct interaction with ILK (Pereira et al, 2009;Berti et al, 2011). The western blotting results confirmed that the phosphorylation of ERK was attenuated by ILK silencing, which might result in the negative regulation of ERCC1 and GST-π.…”

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.…”