6 4 Integrin and Dystroglycan Cooperate to Stabilize the Myelin Sheath

Abstract

Schwann cells integrate signals deriving from the axon and the basal lamina to myelinate peripheral nerves. Integrin α6β4 is a laminin receptor synthesized by Schwann cells and displayed apposed to the basal lamina. α6β4 integrin expression in Schwann cells is induced by axons at the onset of myelination, and rise in adulthood. The β4 chain has a uniquely long cytoplasmic domain that interacts with intermediate filaments such as dystonin, important in peripheral myelination. Furthermore, α6β4 integrin binds peripheral myelin protein 22, whose alteration causes the most common demyelinating hereditary neuropathy. All these data suggest a role for α6β4 integrin in peripheral nerve myelination. Here we show that ablating α6β4 integrin specifically in Schwann cells of transgenic mice does not affect peripheral nerve development, myelin formation, maturation or regeneration. However, consistent with maximal expression in adult nerves, α6β4 integrin-null myelin is more prone to abnormal folding with aging. When the laminin receptor dystroglycan is also ablated, major folding abnormalities occur, associated with acute demyelination in some peripheral nervous system districts. These data indicate that, similar to its role in skin, α6β4 integrin confers stability to myelin in peripheral nerves.

Understanding the mechanisms of entrapment neuropathies

“…33 A recent study of β4 knockout mice suggests that the α6β4 integrin molecule functions in the maintenance of myelin. 27 It is thus possible that integrin signaling plays a critical role in CNC injury.…”

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…Dystrophin and utrophin bind in a noncompetitive manner to F-actin with similar affinities (Rybakova et al 2006). Dystroglycan plays a crucial role in preserving the sarcolemma in the face of muscle contraction/relaxation and is important for development of the Schwann cell nodes of Ranvier, brain cortex laminations, and formation and/or survival of the parietal endoderm (Ervasti and Campbell 1993;Williamson et al 1997;Cohn et al 2002;Moore et al 2002;Nodari et al 2008). Binding occurs among the mucinous O-linked carbohydrate chains located in the mid-neck region of a-dystroglycan with the laminin, perlecan, and agrin LG domains.…”

“…Schwann cell-specific inactivation of the genes coding for b1-integrin, Rac1, and integrin-linked kinase (ILK) were similarly found to cause radial sorting defects whereas inactivation of the genes coding for b4-integrin and dystroglycan (both proteins are expressed late in nerve development) were found to be important for myelin stability and nodal morphogenesis (Feltri et al 2002;Benninger et al 2007;Nodari et al 2008;Pereira et al 2009). An evolving but incomplete model holds that laminin (or basement membrane) ligation of b1 integrins promotes lammellipodial extension and axonal interdigitation through alterations of the activated state of Rac1, Cdc42 and Rho/ Rho kinase.…”

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

“…Sciatic nerves were processed and stained as described (Nodari et al, 2008) using rabbit antibodies against neurofilament (Sigma), goat antibody against -dystroglycan core protein, guinea-pig antibody against 1 integrin (BD Biosciences) and fluorochrome-conjugated secondary antibodies (Jackson ImmunoResearch Laboratories) and viewed with a Leica confocal microscope.…”