Schwann cells require the formation of an organized basal lamina in order to properly ensheath and myelinate axons. Laminins are a group of heterotrimeric extracellular proteins and are critical components within the basal lamina responsible for these processes in peripheral nervous system (PNS). Laminin gamma1 is a component of most laminin isoforms identified to date and is a subunit of laminin-2 (alpha2 beta1 gamma1), the major laminin isoform present in Schwann cell basal lamina. To investigate the function of laminin gamma1 in the PNS, we generated mice homozygous for a laminin gamma1 gene that has a critical exon flanked by IoxP recombination sites (fLAM gamma1) that also carry a Cre recombinase transgene under the control of a Schwann cell-specific promoter, the myelin protein zero (P0) promoter. These mice have disruption of the laminin gamma1 gene in their peripheral nerves, resulting in a severe defect in myelination. The objectives of this proposal are to take advantage of these mice with Schwann cell-specific disruption of laminin gamma1 gene to investigate the role of laminin in the development, myelination, and maintenance of the PNS. To accomplish this goal, we propose three specific aims. First, we will investigate the mechanisms of action of laminin gamma1 in signaling pathways involved in Schwann cell proliferation and apoptosis. Second, we will investigate the mechanisms of action of laminin gamma1 in radial sorting and myelination of PNS. Third, we will investigate the role of laminin gamma1 in the maintenance of peripheral nerves. These experiments will allow us to understand the mechanisms of Schwann cell-basal lamina interactions and may suggest possible new approaches to the therapy of peripheral neuropathies.
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