Mechanisms of Axon-Schwann cell interactions

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In the vertebrate peripheral nervous system (PNS), specialized glial cells called Schwann cells form the myelin sheath, which is required for fast action potential propagation as well as neuronal health and survival. The importance of myelin in normal nervous system function is perhaps best underscored by myelin loss and inefficient remyelination of axon tracts observed in diseases such as demyelinating peripheral neuropathies. Such disruptions of myelin can lead to permanent neuron loss, significant pain and morbidity, and ultimately paralysis. Currently, no treatments exist to prevent demyelination or to enhance remyelination, in part because of our incomplete understanding of the genetic and molecular control of myelination. To identify new regulators of myelinating glial cell development, we previously performed a large-scale forward genetic screen in zebrafish. Through this screen, we identified new mutants in dedicator of cytokinesis (dock1) and previously showed that these global mutants exhibit severe defects in radial sorting and reduced myelination in the PNS during development. Moreover, our preliminary analyses suggest a critical function for Dock1 in nerve repair following injury in adult zebrafish. Dock1 encodes a highly conserved atypical guanine nucleotide exchange factor that can activate the small Rho GTPase Rac1. To date, no role for Dock1 function in Schwann cells has been described, although Rac1 is a known regulator of Schwann cell development. Here, we propose to use zebrafish and mouse models to dissect the mechanisms by which Dock1 controls PNS development and repair. We aim to define the function of Dock1 in Schwann cells (Aim 1), uncover pathways up- and downstream of Dock1 function (Aim 2), and test if Dock1 is required for myelin maintenance or repair following nerve injury in the mammalian PNS (Aim 3). Together, these experiments will define fundamental mechanisms underlying axon-Schwann cell interactions in development, injury, and repair and can lay the foundation for new therapies to treat human neuropathies and peripheral nerve damage.