Investigating the Role of SOX10-Regulated Promoters in Schwann Cells

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

ABSTRACT A major goal of my career as an independent scientist is to understand the mechanisms of demyelinating disease, with the ultimate aim of developing therapies. Inherited demyelinating peripheral neuropathies cause motor and sensory defects in the limbs, and are induced by mutations in genes that are important for the function of myelinating Schwann cells. There are currently no effective treatments for these heterogeneous diseases, which underscores a need for a better understanding of Schwann cell biology. The majority of genes implicated in demyelinating peripheral neuropathy have been characterized as targets of the transcription factor SOX10, which is critical for Schwann cell development and maintenance. Intriguingly, at four loci, including the disease genes MTMR2 and FGD4, we identified SOX10-regulated alternative promoters. These findings gave rise to our hypothesis that regulation of promoter use is a common mechanism of SOX10 function in Schwann cells, and that the identification of similar loci throughout the genome will be a powerful approach toward identifying specific gene products that are important for Schwann cell function. Our preliminary efforts to address this question resulted in the identification of a candidate SOX10-regulated alternative promoter at the CABIN1 locus. CABIN1 is a negative regulator of calcineurin/NFAT signaling in immune cells, but no role has been described in Schwann cells. However, the calcineurin/NFAT signaling axis is required for the differentiation of Schwann cells. Therefore, we hypothesize that a SOX10-regulated CABIN1 isoform regulates Schwann cell differentiation via modulation of calcineurin/NFAT activity. To address these hypotheses, we will: (1) perform a genome-wide computational and functional screen for SOX10-regulated promoters in Schwann cells; and (2) characterize the functional role of CABIN1 in Schwann cells. These endeavors will provide a rich dataset of gene products that are important in Schwann cells and will enhance our understanding of a signaling cascade that is important for Schwann cell development. Importantly, the completion of this proposal will mediate the development of technical and analytical skills necessary for me to succeed as an academic scientist studying the genetic and molecular mechanisms of myelination.