Peripheral neuropathies are a group of diseases characterized by impaired motor function and sensory loss in the extremities. Between 2-8% of the general population is affected with a peripheral neuropathy, making these diseases a significant public health concern. More than 80% of patients with inherited peripheral neuropathy carry mutations in genes encoding proteins critical for myelinating Schwann cells-a cell population that insulates and provides trophic factors to peripheral nerve axons. Currently, we have a very limited understanding of the transcriptional hierarchies involved in Schwann cell development and homeostasis. The SRY-box containing gene 10 (SOX10) encodes a transcription factor that is essential for Schwann cell development and function. Importantly, mutations in SOX10 and in loci regulated by SOX10 have been implicated in demyelinating peripheral neuropathies. Thus, the identification and characterization of novel SOX10 target loci will provide additional candidate genes for demyelinating peripheral neuropathies and key knowledge regarding Schwann cell biology. Toward this, we will: (1) Perform genome-wide identification of SOX10 target loci in myelinating Schwann cells;(2) Determine if SOX10 is necessary for the expression of two novel target genes (SH3KBP1 and BCAS3) in myelinating Schwann cells;and (3) Characterize the function of SH3KBP1 and BCAS3 in myelinating Schwann cells.

Public Health Relevance

Schwann cells are a critical component of peripheral nerves-structures essential for mobility and sensation in the hands and feet. Remarkably little is known about gene regulation in Schwann cells. The major goal of this proposal is to address this lack of knowledge through genome-wide identification of novel genes and proteins expressed in Schwann cells and determining how they contribute to Schwann cell function. These studies will provide key information on the function of peripheral nerves and associated human diseases such as peripheral neuropathy and multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073748-02
Application #
8234039
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$306,141
Indirect Cost
$109,266
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Fogarty, Elizabeth A; Brewer, Megan H; Rodriguez-Molina, Jose F et al. (2016) SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2. Hum Mol Genet 25:3925-3936
Gopinath, Chetna; Law, William D; Rodríguez-Molina, José F et al. (2016) Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation. BMC Genomics 17:887
Lopez-Anido, Camila; Poitelon, Yannick; Gopinath, Chetna et al. (2016) Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development. Hum Mol Genet 25:3055-3069
Abrams, Alexander J; Hufnagel, Robert B; Rebelo, Adriana et al. (2015) Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet 47:926-32
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