Expression of laminin Receptors in Schwann cell differentiation: Evidence for distinct roles

Neuropathology Unit, Department of Neuroscience and DIBIT, San Raffaele Scientific Institute, 20132 Milan, Italy.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2003; 23(13):5520-30.
Source: PubMed

ABSTRACT Schwann cells require laminin-2 throughout nerve development, because mutations in the alpha2 chain in dystrophic mice interfere with sorting of axons before birth and formation of myelin internodes after birth. Mature Schwann cells express several laminin receptors, but their expression and roles in development are poorly understood. Therefore, we correlated the onset of myelination in nerve and synchronized myelinating cultures to the appearance of integrins and dystroglycan in Schwann cells. Only alpha6beta1 integrin is expressed before birth, whereas dystroglycan and alpha6beta4 integrin appear perinatally, just before myelination. Although dystroglycan is immediately polarized to the outer surface of Schwann cells, alpha6beta4 appears polarized only after myelination. We showed previously that Schwann cells lacking beta1 integrin do not relate properly to axons before birth. Here we show that the absence of beta1 before birth is not compensated by other laminin receptors, whereas coexpression of both dystroglycan and beta4 integrin is likely required for beta1-null Schwann cells to myelinate after birth. Finally, both beta1-null and dystrophic nerves contain bundles of unsorted axons, but they are predominant in different regions: in spinal roots in dystrophic mice and in nerves in beta1-null mice. We show that differential compensation by laminin-1, but not laminin receptors may partially explain this. These data suggest that the action of laminin is mediated by beta1 integrins during axonal sorting and by dystroglycan, alpha6beta1, and alpha6beta4 integrins during myelination.

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Available from: Antonello Villa, Sep 29, 2015
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    • "Transgenic mice which possess a mutation in the c1 laminin gene of Schwann cells have severely disrupted peripheral nerves, Schwann cells do not extend processes between axons, do not produce a continuous basement membrane, show reduced sodium channel clustering at nodes of Ranvier, and have reduced nerve conduction velocity (Chen and Strickland, 2003; Yu et al., 2005). In the peripheral nerves of laminin a2 mutant mice, the basement membrane is also disrupted, axons have reduced Schwann cell ensheathment and myelination; however , the phenotype is perhaps relatively mild, as there is a compensatory increase in laminins a4 and a1 isoforms (Patton et al., 1997; Previtali et al., 2003b). The importance of laminin–integrin interaction in Schwann cells in radial sorting, axonal maturation and myelination is described in further detail by Colognato and Tzvetanova (2011). "
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    ABSTRACT: The somatosensory nervous system is responsible for the transmission of a multitude of sensory information from specialized receptors in the periphery to the central nervous system. Sensory afferents can potentially be damaged at several sites: in the peripheral nerve; the dorsal root; or the dorsal columns of the spinal cord; and the success of regeneration depends on the site of injury. The regeneration of peripheral nerve branches following injury is relatively successful compared to central branches. This is largely attributed to the presence of neurotrophic factors and a Schwann cell basement membrane rich in permissive extracellular matrix (ECM) components which promote axonal regeneration in the peripheral nerve. Modulation of the ECM environment and/or neuronal integrins may enhance regenerative potential of sensory neurons following peripheral or central nerve injury or disease. This review describes the interactions between integrins and ECM molecules (particularly the growth supportive ligands, laminin, and fibronectin; and the growth inhibitory chondroitin sulfate proteoglycans (CSPGs)) during development and regeneration of sensory neurons following physical injury or neuropathy.
    Developmental Neurobiology 11/2011; 71(11):1054-72. DOI:10.1002/dneu.20950 · 3.37 Impact Factor
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    • "Laminins are also recognized by 'non-integrin' receptors including dystroglycan. In peripheral nerves, laminins expressed in the basal lamina play a pivotal role in Schwann cell-axon interactions (Uziyel et al. 2000; Wallquist et al. 2005; Yang et al. 2005), acting both through Schwann cell integrin and dystroglycan receptors at the different steps of myelin formation (Feltri et al. 2002; Previtali et al. 2003). For the CNS, blocking antibodies to dystroglycan receptors do not affect oligodendrocyte survival but prevent oligodendroglial production of complex membrane sheets and myelin segments when added on dorsal root ganglia neurons in vitro (Colognato et al. 2007), suggesting that dystroglycan receptors may have a specific role in the regulation of terminal stages of myelination. "
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    ABSTRACT: J. Neurochem. (2010) 114, 1243–1260. In multiple sclerosis, CNS demyelination is often followed by spontaneous repair, mostly achieved by adult oligodendrocyte precursor cells. Extent of this myelin repair differs, ranging from very low, limited to the plaque border, to extensive, with remyelination throughout the ‘shadow plaques.’ In addition to restoring neuronal connectivity, new myelin is neuroprotective. It reduces axonal loss and thus disability progression. Reciprocal communication between neurons and oligodendrocytes is essential for both myelin biogenesis and myelin repair. Hence, deciphering neuron-oligodendrocyte communication is not only important for understanding myelination per se, but also the pathophysiology that underlies demyelinating diseases and the development of innovative therapeutic strategies.
    Journal of Neurochemistry 09/2010; 114(5):1243-60. DOI:10.1111/j.1471-4159.2010.06831.x · 4.28 Impact Factor
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    • "LMα2 chain receptors present in peripheral nerve include dystroglycan, integrins α6β1, α7β1 and possibly integrin α6β4 [16], [17]. Dystroglycan, β1 and β4 integrin subunits have been shown to be important for different aspects of myelination and morphology of peripheral nerves, as revealed by conditional disruption of their genes in Schwann cells [18]–[20]. "
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    ABSTRACT: Laminin alpha2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that laminin alpha1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin alpha2 chain, alpha1 chain binds the receptors by separate domains; laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the laminin alpha1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system. Here, we provide insights into the functions of laminin alpha1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin alpha1 chain that lacks the dystroglycan binding LG4-5 domains in alpha2 chain deficient mice resulted in prolonged lifespan and improved health. Importantly, diaphragm and heart muscles were corrected, whereas limb muscles were dystrophic, indicating that different muscles have different requirements for LG4-5 domains. Furthermore, the regenerative capacity of the skeletal muscle did not depend on laminin alpha1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly. These results show that laminin alpha1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization of future medical treatment for MDC1A patients.
    PLoS ONE 07/2010; 5(7):e11549. DOI:10.1371/journal.pone.0011549 · 3.23 Impact Factor
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