Coordinate control of axon defasciculation and myelination by laminin-2 and -8

Abstract

Schwann cells form basal laminae (BLs) containing laminin-2 (Ln-2; heterotrimer α2β1γ1) and Ln-8 (α4β1γ1). Loss of Ln-2 in humans and mice carrying α2-chain mutations prevents developing Schwann cells from fully defasciculating axons, resulting in partial amyelination. The principal pathogenic mechanism is thought to derive from structural defects in Schwann cell BLs, which Ln-2 scaffolds. However, we found loss of Ln-8 caused partial amyelination in mice without affecting BL structure or Ln-2 levels. Combined Ln-2/Ln-8 deficiency caused nearly complete amyelination, revealing Ln-2 and -8 together have a dominant role in defasciculation, and that Ln-8 promotes myelination without BLs. Transgenic Ln-10 (α5β1γ1) expression also promoted myelination without BL formation. Rather than BL structure, we found Ln-2 and -8 were specifically required for the increased perinatal Schwann cell proliferation that attends myelination. Purified Ln-2 and -8 directly enhanced in vitro Schwann cell proliferation in collaboration with autocrine factors, suggesting Lns control the onset of myelination by modulating responses to mitogens in vivo.

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…During this process, immature Schwann cells assemble basement membranes on their abaxonal surfaces. Mutations that prevent expression of the laminin g1, a2, and a4 subunits, or that remove the laminin a2-LN domain (dy2J), result in radial sorting defects (Sunada et al 1995a;Miyagoe et al 1997;Wallquist et al 2005;Yang et al 2005). The Lma2 deficient mice provide models of the nerve pathology seen in human MDC1A congenital muscular dystrophy.…”

Regulation of Schwann cell function by the extracellular matrix

“…During late embryonic to perinatal stages (E15 to P0 in mice), immature Schwann cells proliferate vigorously to rearrange, sort, and ensheath axons (Stewart et al, 1993) In laminin g1 mutant and dy2J/a4 double mutant mice, Schwann cell proliferation is dramatically decreased during this developmental stage (Yang et al, 2005;Yu et al, 2005) (Fig. 2A).…”

Eph receptor expression defines midline boundaries for ephrin‐positive migratory neurons in the enteric nervous system of Manduca sexta

“…Ultrathin (90 nm) sections were taken at designated locations along the midgut and isolated on Formvar-coated grids (Electron Microscopy Sciences, Fort Washington, PA). The sections were then imaged on a Jeol JEM-100CX II transmission electron microscope at magnifications ranging from 6,000-20,000X (Yang et al, 2005). Scanning electron microscopy was performed as previously described (Copenhaver & Taghert, 1989a;Copenhaver and Taghert, 1989b).…”