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Genetic background of Prop1(df) mutants provides remarkable protection against hypothyroidism-induced hearing impairment.

Fang Q, Giordimaina AM, Dolan DF, Camper SA, Mustapha M - J. Assoc. Res. Otolaryngol. (2011)

Bottom Line: Using embryo transfer, we discovered that factors intrinsic to the fetus are the major contributor to this difference, not maternal effects.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.Prop1(df) mutants exhibit persistent, abnormal expression of otoferlin in apical OHC, suggesting delayed maturation of synaptic function.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Michigan, 4945 Buhl, 1241 E Catherine St., Ann Arbor, MI 48109-5618, USA.

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.

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Prop1df mutants exhibit mild OHC dysfunction with normal expression of KCNQ4 and prestin. A DPOAEs were measured in live 4-week and 7-week-old wild-type and Prop1df mutant mice (black circles and white squares, respectively), and compared with DPOAEs of postmortem animals (dotted and dashed line). Data are shown for the 12 and 24 kHz frequencies. N = 3 for each genotype group of 4-week-old mice and n = 6 for 7-week-old ones. B, C KCNQ4 immunoreactivity is normal in OHCs (arrows) of mutant mice relative to wild type. Frozen sections obtained from P28 wild-type and mutant mice were stained for KCNQ4 (red). Nuclei were stained with DAPI (blue). D, E Prestin expression and localization was analyzed by staining frozen sections from wild-type and Prop1df mutants at P28 with prestin-specific antibodies (red). Nuclei were labeled using DAPI (blue). Arrows identify rows of outer hair cells. Scale bars: 10 μm.
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Fig3: Prop1df mutants exhibit mild OHC dysfunction with normal expression of KCNQ4 and prestin. A DPOAEs were measured in live 4-week and 7-week-old wild-type and Prop1df mutant mice (black circles and white squares, respectively), and compared with DPOAEs of postmortem animals (dotted and dashed line). Data are shown for the 12 and 24 kHz frequencies. N = 3 for each genotype group of 4-week-old mice and n = 6 for 7-week-old ones. B, C KCNQ4 immunoreactivity is normal in OHCs (arrows) of mutant mice relative to wild type. Frozen sections obtained from P28 wild-type and mutant mice were stained for KCNQ4 (red). Nuclei were stained with DAPI (blue). D, E Prestin expression and localization was analyzed by staining frozen sections from wild-type and Prop1df mutants at P28 with prestin-specific antibodies (red). Nuclei were labeled using DAPI (blue). Arrows identify rows of outer hair cells. Scale bars: 10 μm.

Mentions: Cochlear OHCs are unique in their electromotility and work as a cochlear amplifier in sound processing (Ospeck et al. 2003). DPOAE is used as a standard audiometric technique to measure OHC function of amplification. At 4 weeks of age, Prop1df/df mutants have DPOAE responses (geometric means of the primary tones) at 12 or 24 kHz that are indistinguishable from the noise floor in postmortem mutant or wild-type mice (Fig. 3A). By 7 weeks old, Prop1df/df mutants have improved, but only have about half of the normal DPOAE at 24 kHz (Fig. 3A). At 12 weeks old, the DPOAE response of Prop1df/df mutants are still significantly lower than the wild-type mice (data not shown). The maturation process of DPOAE in mice normally begins at 11 days old and obtains the adult-like pattern by 4 weeks (Narui et al. 2009). This demonstrates that Prop1df/df mutant cochlea have delayed development of OHC function with persistent deficiency at 12 wks. ABR measurements improve between 4 and 7 weeks of age (Fig. 1), suggesting that the persistent OHC dysfunction could be a contributor to the mild hearing impairment in Prop1df/df mutants.FIG. 3


Genetic background of Prop1(df) mutants provides remarkable protection against hypothyroidism-induced hearing impairment.

Fang Q, Giordimaina AM, Dolan DF, Camper SA, Mustapha M - J. Assoc. Res. Otolaryngol. (2011)

Prop1df mutants exhibit mild OHC dysfunction with normal expression of KCNQ4 and prestin. A DPOAEs were measured in live 4-week and 7-week-old wild-type and Prop1df mutant mice (black circles and white squares, respectively), and compared with DPOAEs of postmortem animals (dotted and dashed line). Data are shown for the 12 and 24 kHz frequencies. N = 3 for each genotype group of 4-week-old mice and n = 6 for 7-week-old ones. B, C KCNQ4 immunoreactivity is normal in OHCs (arrows) of mutant mice relative to wild type. Frozen sections obtained from P28 wild-type and mutant mice were stained for KCNQ4 (red). Nuclei were stained with DAPI (blue). D, E Prestin expression and localization was analyzed by staining frozen sections from wild-type and Prop1df mutants at P28 with prestin-specific antibodies (red). Nuclei were labeled using DAPI (blue). Arrows identify rows of outer hair cells. Scale bars: 10 μm.
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Related In: Results  -  Collection

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Fig3: Prop1df mutants exhibit mild OHC dysfunction with normal expression of KCNQ4 and prestin. A DPOAEs were measured in live 4-week and 7-week-old wild-type and Prop1df mutant mice (black circles and white squares, respectively), and compared with DPOAEs of postmortem animals (dotted and dashed line). Data are shown for the 12 and 24 kHz frequencies. N = 3 for each genotype group of 4-week-old mice and n = 6 for 7-week-old ones. B, C KCNQ4 immunoreactivity is normal in OHCs (arrows) of mutant mice relative to wild type. Frozen sections obtained from P28 wild-type and mutant mice were stained for KCNQ4 (red). Nuclei were stained with DAPI (blue). D, E Prestin expression and localization was analyzed by staining frozen sections from wild-type and Prop1df mutants at P28 with prestin-specific antibodies (red). Nuclei were labeled using DAPI (blue). Arrows identify rows of outer hair cells. Scale bars: 10 μm.
Mentions: Cochlear OHCs are unique in their electromotility and work as a cochlear amplifier in sound processing (Ospeck et al. 2003). DPOAE is used as a standard audiometric technique to measure OHC function of amplification. At 4 weeks of age, Prop1df/df mutants have DPOAE responses (geometric means of the primary tones) at 12 or 24 kHz that are indistinguishable from the noise floor in postmortem mutant or wild-type mice (Fig. 3A). By 7 weeks old, Prop1df/df mutants have improved, but only have about half of the normal DPOAE at 24 kHz (Fig. 3A). At 12 weeks old, the DPOAE response of Prop1df/df mutants are still significantly lower than the wild-type mice (data not shown). The maturation process of DPOAE in mice normally begins at 11 days old and obtains the adult-like pattern by 4 weeks (Narui et al. 2009). This demonstrates that Prop1df/df mutant cochlea have delayed development of OHC function with persistent deficiency at 12 wks. ABR measurements improve between 4 and 7 weeks of age (Fig. 1), suggesting that the persistent OHC dysfunction could be a contributor to the mild hearing impairment in Prop1df/df mutants.FIG. 3

Bottom Line: Using embryo transfer, we discovered that factors intrinsic to the fetus are the major contributor to this difference, not maternal effects.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.Prop1(df) mutants exhibit persistent, abnormal expression of otoferlin in apical OHC, suggesting delayed maturation of synaptic function.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Michigan, 4945 Buhl, 1241 E Catherine St., Ann Arbor, MI 48109-5618, USA.

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.

Show MeSH
Related in: MedlinePlus