Interaction of NRG1-III and laminin 211 signaling within Schwann cells to achieve proper peripheral nerve radial sorting and myelination
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Proper ensheathment and myelination of axons within the Peripheral Nervous System require Schwann Cell (SC) interaction with both axons and the extracellular matrix (ECM). SCs rely on these signals in order to recognize and ensheath axons of a large enough caliber, a process called radial sorting. Once sorted, SCs use these signals to form myelin wraps of appropriate thickness around the axons. This peripheral nerve myelination serves to increase action potential propagation speed, while also providing support to axons. Improper myelin formation and function lead to a variety of detrimental diseases. The neuronal protein crucial for these SC processes is neuregulin 1 type III (NRG1-III), while the crucial ECM components are laminins. Previous findings with genetically modified mice have suggested that laminins and NRG1-III interact to regulate both radial sorting and myelination. Specifically, it appears that laminin 211 (Lm211) works to inhibit NRG1-III pathways during radial sorting. After radial sorting, Lm211 appears to activate parallel pathways that act as both positive and negative regulators of the NRG1-III pathway to affect myelination. The current study focuses on investigation of the mechanism underlying NRG1-III and Lm211 interaction in both radial sorting and myelination. Current findings suggest that in radial sorting Lm211 limits activation of cAMP and PKA to work as a brake pedal on the NRG1-III pathway, thus allowing radial sorting to occur properly prior to the onset of myelination. Excess PKA activity present in Lm211 null mice leads to increased Krox-20 expression, with altered localization, and increased Oct-6 linked to larger undifferentiated SC numbers. It appears that Lm211's both positive and negative effects on myelination are due to differential activation of laminin receptors. Investigation is currently focused on integrin α6β4 as the potential laminin receptor expressed on SC's which Lm211 uses to limit myelination via inhibition of the NRG1-III pathway.