Impact of Schwann Cell Pathology on Axon Structure and Function

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Reciprocal interactions between axons and Schwann cells (SCs) drive the formation, function, and maintenance of myelinated nerves, which are essential for effective saltatory conduction and neurologic function. Extrinsic signals from the axon and the basal lamina (BL) cooperatively drive expression of a series of SC transcription factors (TFs), culminating in the expression of Egr2, the master regulator of PNS myelination. Egr2 is required for SCs to advance from the promyelinating stage, when they wrap axons once, to myelination, when they upregulate myelin components and form the multilamellar myelin sheath. Myelinating SCs in turn re-organize axons into distinct domains, in particular the node of Ranvier, and increase axon size. These collective changes enable and optimize action potential propagation by saltatory conduction. The importance of this regulation of axon biology by SCs is underscored by the disability associated with acquired and inherited (e.g., Charcot Marie Tooth (CMT) disorders of myelinating SCs (mSCs). CMTs that result from various SC mutations cause de/dysmyelination characterized by slow nerve conduction velocity (NCV), often with nerve conduction block (NCB). Pathologic features of CMTs typically include inflammation, hypertrophic changes, reduced axon diameters and (distal) axon loss. The resulting neurological disability can range from minor to severe. How SC defects drive this array of cellular pathologies and what mechanisms underlie the clinical spectrum of CMTs are key questions with important translational implications. To interrogate how SC pathology impacts axon biology and leads to clinical defects, we are characterizing mice in which two key SC proteins, Egr2 and the G coupled protein receptor, Gpr126 have been deleted. Conditional knockouts (cKOs) of either of these proteins arrest SCs at the promyelinating stage and blocks their ability to form myelin. Yet these mice have very different phenotypes: Gpr126 cKOs are mildly affected and have a normal life span whereas Egr2 cKOs are progressively paralyzed and moribund by 3-4 months of age. As expected, NCV is markedly slow in both mutants. However, only the Egr2 cKOs exhibit frank NCB, a likely driver of their severe disability. Correspondingly, these mutants have very distinct nerve pathologies. Egr2 cKOs nerves are markedly inflamed, hypertrophic, and their axons are significantly smaller as compared to Gpr126 cKOs. To further elucidate differences between these mutants, we will investigate: i) the role of inflammation in their respective phenotypes and why these dysmyelinating SCs differentially activate inflammation, ii) examine the mechanisms by which these SC mutations regulate axon diameter and iii) use single nuclei RNAseq to characterize changes in the transcriptomes of SCs that impact axon biology and function in nerve conduction. These studies should provide important new insights into how SC pathology impacts axon biology and function and may lead to new therapeutic strategies to ameliorate disability in disorders of myelinated fibers.