title: SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2.
abstract: Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin-related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves. Previous reports indicate that MTMR2 is ubiquitously expressed making it unclear how loss of this gene causes a Schwann cell-specific phenotype. To address this, we performed computational and functional analyses at MTMR2 to identify transcriptional regulatory elements important for Schwann cell expression. Through these efforts, we identified an alternative, SOX10-responsive promoter at MTMR2 that displays strong regulatory activity in immortalized rat Schwann (S16) cells. This promoter directs transcription of a previously unidentified MTMR2 transcript that is enriched in mouse Schwann cells compared to immortalized mouse motor neurons (MN-1), and is predicted to encode an N-terminally truncated protein isoform. The expression of the endogenous transcript is induced in a heterologous cell line by ectopically expressing SOX10, and is nearly ablated in Schwann cells by impairing SOX10 function. Intriguingly, overexpressing the two MTMR2 protein isoforms in HeLa cells revealed that both localize to nuclear puncta and the shorter isoform displays higher nuclear localization compared to the longer isoform. Combined, our data warrant further investigation of the truncated MTMR2 protein isoform in Schwann cells and in CMT4B1 pathogenesis.
authors.affiliation: Neuroscience Graduate Program.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fogarty
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Brewer
authors.affiliation: Cellular and Molecular Pathology (CMP) Program.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Rodriguez-Molina
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Law
authors.affiliation: Cellular and Molecular Pathology (CMP) Program.
authors.forename: Ki H
authors.initials: KH
authors.lastname: Ma
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Steinberg
authors.affiliation: Waisman Center.|Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: John
authors.initials: J
authors.lastname: Svaren
authors.affiliation: Neuroscience Graduate Program antonell@umich.edu.|Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.|Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009186:Myelin Sheath / Q000235:genetics; D010525:Peripheral Nerves / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D055757:SOXE Transcription Factors / Q000235:genetics*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C408986:MTMR2 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor