title: Genetic background of Prop1(df) mutants provides remarkable protection against hypothyroidism-induced hearing impairment.
abstract: Hypothyroidism is a cause of genetic and environmentally induced deafness. The sensitivity of cochlear development and function to thyroid hormone (TH) mandates understanding TH action in this sensory organ. Prop1(df) and Pou1f1(dw) mutant mice carry mutations in different pituitary transcription factors, each resulting in pituitary thyrotropin deficiency. Despite the same lack of detectable serum TH, these mutants have very different hearing abilities: Prop1(df) mutants are mildly affected, while Pou1f1(dw) mutants are completely deaf. Genetic studies show that this difference is attributable to the genetic backgrounds. Using embryo transfer, we discovered that factors intrinsic to the fetus are the major contributor to this difference, not maternal effects. We analyzed Prop1(df) mutants to identify processes in cochlear development that are disrupted in other hypothyroid animal models but protected in Prop1(df) mutants by the genetic background. The development of outer hair cell (OHC) function is delayed, but Prestin and KCNQ4 immunostaining appear normal in mature Prop1(df) mutants. The endocochlear potential and KCNJ10 immunostaining in the stria vascularis are indistinguishable from wild type, and no differences in neurofilament or synaptophysin staining are evident in Prop1(df) mutants. The synaptic vesicle protein otoferlin normally shifts expression from OHC to IHC as temporary afferent fibers beneath the OHC regress postnatally. Prop1(df) mutants exhibit persistent, abnormal expression of otoferlin in apical OHC, suggesting delayed maturation of synaptic function. Thus, the genetic background of Prop1(df) mutants is remarkably protective for most functions affected in other hypothyroid mice. The Prop1(df) mutant is an attractive model for identifying the genes that protect against deafness.
authors.affiliation: Department of Human Genetics, University of Michigan, 4945 Buhl, 1241 E Catherine St., Ann Arbor, MI, 48109-5618, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Health Behavior & Health Education Department, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Giordimaina
authors.affiliation: Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Dolan
authors.affiliation: Department of Human Genetics, University of Michigan, 4945 Buhl, 1241 E Catherine St., Ann Arbor, MI, 48109-5618, USA. scamper@umich.edu.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Mustapha
mesh_terms: D000818:Animals; D005260:Female; D018072:Hair Cells, Auditory, Outer / Q000502:physiology; D034381:Hearing Loss / Q000517:prevention & control*; D018398:Homeodomain Proteins / Q000235:genetics*; D007037:Hypothyroidism / Q000150:complications*; D051656:KCNQ Potassium Channels / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000032:analysis; D011247:Pregnancy; D013963:Thyroid Hormones / Q000502:physiology; D050817:Transcription Factor Pit-1 / Q000235:genetics; D000098854:Kcnj10 Channel
chemical_list: D018398:Homeodomain Proteins; D051656:KCNQ Potassium Channels; D008565:Membrane Proteins; D024661:Potassium Channels, Inwardly Rectifying; D013963:Thyroid Hormones; D050817:Transcription Factor Pit-1; D000098854:Kcnj10 Channel; C492167:Kcnq4 protein, mouse; C494185:Pou1f1 protein, mouse; C102134:Prophet of Pit-1 protein; C516233:otoferlin protein, mouse