TY - JOUR
T1 - A mouse model of MIR-96, MIR-182 and MIR-183 misexpression implicates MIRNAs in cochlear cell fate and homeostasis
AU - Weston, Michael D.
AU - Tarang, Shikha
AU - Pierce, Marsha L.
AU - Pyakurel, Umesh
AU - Rocha-Sanchez, Sonia M.
AU - McGee, Jo Ann
AU - Walsh, Edward J.
AU - Soukup, Garrett A.
N1 - Funding Information:
Excellent technical support was provided by Lane H. Beisel, Megan Korte, Songila Doi, Xiaona Huang and luciferase experimental expertise by Tim Hallman and Jodi Monahan. Additional expert technical support was also provided by the UNMC MicroArray Core Facility (James Eudy, Director), the UNMC Transgenic Core (Judy Stribley) and the UNMC Advanced Microscopy Core Facility (Janice A. Taylor, James R. Talaska). Mouse lines used in the study were maintained at Creighton University’s Animal Resource Facility, whose infrastructure was improved through a grant by NIH/NCRR G20RR024001. The UNMC Advanced Microscopy Core Facility was supported by infrastructure grants provided by the Nebraska Research Initiative, the Fred and Pamela Buffet Cancer Center (P30 CA036727, and an Institutional Development Award (IDea) from the NIGMS of the NIH, grant number P30 GM106397. This work received past support through NIH/NIDCD F32DC008253 (M.D.W), COBRE grant NIH/NCRR 5P20RR018788-/NIH/NIGMS 8P20GM103471 (Shelley D. Smith, PI), by the Physiology Phenotyping Core of COBRE grant NIH/NIGMS 5P30GM110768 Subproject 6083 (E.J.W), by the Nebraska Health Care Funding Act LB692 (M.D.W) and current funding through NIH/NIDCD R15DC014813-01A1 (M.D.W, S.M.R.-S.) and 1R21OD019745-01A1 (S.M.R.-S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Germline mutations in Mir96, one of three co-expressed polycistronic miRNA genes (Mir96, Mir182, Mir183), cause hereditary hearing loss in humans and mice. Transgenic FVB/NCrl-Tg(GFAP-Mir183,Mir96,Mir182)MDW1 mice (Tg1MDW), which overexpress this neurosensory-specific miRNA cluster in the inner ear, were developed as a model system to identify, in the aggregate, target genes and biologic processes regulated by the miR-183 cluster. Histological assessments demonstrate Tg1MDW/1MDW homozygotes have a modest increase in cochlear inner hair cells (IHCs). Affymetrix mRNA microarray data analysis revealed that downregulated genes in P5 Tg1MDW/1MDW cochlea are statistically enriched for evolutionarily conserved predicted miR-96, miR-182 or miR-183 target sites. ABR and DPOAE tests from 18 days to 3 months of age revealed that Tg1MDW/1MDW homozygotes develop progressive neurosensory hearing loss that correlates with histologic assessments showing massive losses of both IHCs and outer hair cells (OHCs). This mammalian miRNA misexpression model demonstrates a potency and specificity of cochlear homeostasis for one of the dozens of endogenously co-expressed, evolutionally conserved, small non-protein coding miRNA families. It should be a valuable tool to predict and elucidate miRNA-regulated genes and integrated functional gene expression networks that significantly influence neurosensory cell differentiation, maturation and homeostasis.
AB - Germline mutations in Mir96, one of three co-expressed polycistronic miRNA genes (Mir96, Mir182, Mir183), cause hereditary hearing loss in humans and mice. Transgenic FVB/NCrl-Tg(GFAP-Mir183,Mir96,Mir182)MDW1 mice (Tg1MDW), which overexpress this neurosensory-specific miRNA cluster in the inner ear, were developed as a model system to identify, in the aggregate, target genes and biologic processes regulated by the miR-183 cluster. Histological assessments demonstrate Tg1MDW/1MDW homozygotes have a modest increase in cochlear inner hair cells (IHCs). Affymetrix mRNA microarray data analysis revealed that downregulated genes in P5 Tg1MDW/1MDW cochlea are statistically enriched for evolutionarily conserved predicted miR-96, miR-182 or miR-183 target sites. ABR and DPOAE tests from 18 days to 3 months of age revealed that Tg1MDW/1MDW homozygotes develop progressive neurosensory hearing loss that correlates with histologic assessments showing massive losses of both IHCs and outer hair cells (OHCs). This mammalian miRNA misexpression model demonstrates a potency and specificity of cochlear homeostasis for one of the dozens of endogenously co-expressed, evolutionally conserved, small non-protein coding miRNA families. It should be a valuable tool to predict and elucidate miRNA-regulated genes and integrated functional gene expression networks that significantly influence neurosensory cell differentiation, maturation and homeostasis.
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U2 - 10.1038/s41598-018-21811-1
DO - 10.1038/s41598-018-21811-1
M3 - Article
C2 - 29476110
AN - SCOPUS:85042549261
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 3569
ER -