Myelination allows rapid propagation of action potentials in the nervous system. Dys- and demyelinating disorders are among the most common neurological pathologies affecting young adults. Myelinating glial cells such as Schwann cells of the peripheral nervous system undergo stage specific changes in morphology that enable them to elaborate myelin around an axon. The signaling pathways that regulate actin dynamics in response to extrinsic axonal and extracellular matrix cues are largely unknown. We recently reported that activation of ErbB and B1 integrin receptors induces phosphorylation of Schwannomin, the Neurofibromatosis type 2 tumor suppressor. Schwannomin links receptors to the actin cytoskeleton and modulates the activity of Cdc42/RacGTPase. Thus it is positioned to link receptor activity to actin dynamics and trigger changes in cellular morphology needed for myelination. We hypothesize that Sch modulates actin polymerization through a p21activated kinase (PAK) - LIM kinase - cofilin pathway.
In Aim 1, we propose to elucidate the function of cofilin during Schwann cell myelination. We will compare the ability normal and cofilin-deficient Schwann cells to myelinate axons in vitro.
In Aim 2, we will assess whether neuregulin and laminin regulate LlMK and cofilin phosphorylation. We will determine whether cofilin is needed for Schwann cells to remodel their plasma membrane in response to NRG and laminin stimulation by conducting live imaging experiments with normal and cofilin-deficient Schwann cells. The immediate outcome of this work will be to identify a novel pathway used by Schwann cells to produce receptor specific changes in morphology associated with myelination. If successful, this work will provide the first complete map of a signaling cascade initiated by axonal and basal lamina ligands that terminates at the final downstream effector protein, actin. This information will impact the identification of increasingly specific drug targets for development of single and combinatorial therapies for myelinating disorders and other Schwann cell disorders such as Neurofibromatosis and Schwannomatosis.
This proposed study investigates molecular and cellular mechanisms involved in forming myelin in the peripheral nervous system. The results will provide a foundation for understanding the pathologies associated with not only myelin disorders but also tumor disorders involving Schwann cells, such as Neurofibromatosis.
