Glial-Specific Deletion of Med12 Results in Rapid Hearing Loss via Degradation of the Stria Vascularis.

Autor:	Huang TW; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030., Iyer AA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.; Program in Genetics & Genomics, Baylor College of Medicine, Houston, Texas 77030., Manalo JM; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030., Woo J; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030., Bosquez Huerta NA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030.; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030., McGovern MM; Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030., Schrewe H; Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany., Pereira FA; Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030.; Department of Otolaryngology, Baylor College of Medicine, Houston, Texas 77030., Groves AK; Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030.; Program in Genetics & Genomics, Baylor College of Medicine, Houston, Texas 77030., Ohlemiller KK; Department of Otolaryngolgy, Central Institute for the Deaf, Fay and Carl Simons Center for Biology of Hearing and Deafness, Washington University in St. Louis, St. Louis, Missouri 63110., Deneen B; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030 deneen@bcm.edu.; Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030.; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030.; Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2021 Aug 25; Vol. 41 (34), pp. 7171-7181. Date of Electronic Publication: 2021 Jul 12.
DOI:	10.1523/JNEUROSCI.0070-21.2021
Abstrakt:	Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology. Surprisingly, behavioral studies revealed rapid hearing loss after adult deletion of Med12 that was confirmed by a complete abrogation of auditory brainstem responses. Cellular analysis of the cochlea revealed degeneration of the stria vascularis, in conjunction with disorganization of basal cells adjacent to the spiral ligament and downregulation of key cell adhesion proteins. Physiologic analysis revealed early changes in endocochlear potential, consistent with strial-specific defects. Together, our studies reveal that Med12 regulates auditory function in the adult by preserving the structural integrity of the stria vascularis. SIGNIFICANCE STATEMENT Mutations in Mediator protein complex subunit 12 (Med12) are associated with X-linked intellectual disability syndromes and hearing loss. Using temporal-conditional genetic approaches in CNS glia, we found that loss of Med12 results in severe hearing loss in adult animals through rapid degeneration of the stria vascularis. Our study describes the first animal model that recapitulates hearing loss identified in Med12-related disorders and provides a new system in which to examine the underlying cellular and molecular mechanisms of Med12 function in the adult nervous system. (Copyright © 2021 the authors.)
Databáze:	MEDLINE
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