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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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Gestational and neonatal environments do not account for different hearing abilities of Prop1df and Pou1f1dw mutants. Pups born from surrogate mothers (designated as “Genotype_S”) were tested by ABR. The hearing deficits of Prop1df/df_S and Pou1f1dw/dw_S are significantly different (P < 0.001). For each group, four mice were tested (n = 4).
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Fig2: Gestational and neonatal environments do not account for different hearing abilities of Prop1df and Pou1f1dw mutants. Pups born from surrogate mothers (designated as “Genotype_S”) were tested by ABR. The hearing deficits of Prop1df/df_S and Pou1f1dw/dw_S are significantly different (P < 0.001). For each group, four mice were tested (n = 4).

Mentions: To determine the degree to which maternal effects contribute to the different degrees of hearing impairment in Prop1df/df and Pou1f1dw/dw mutants, fertilized eggs with all genotypes from both strains were transplanted into the uteri of B6/D2 surrogate mothers, which would provide common gestation and lactation environments for both mutants. We chose the mothers of the B6/D2 strain as surrogates because they have hybrid vigor and exhibit good mothering instincts. The hearing ability of the progeny born to the surrogates was tested by ABR at 4 weeks of age, including Prop1df/df_S and Pou1f1dw/dw_S mutants as well as wild types from each strain. The hearing deficits of Prop1df/df_S and Pou1f1dw/dw_S mutants are significantly different from their normal littermates, also born to surrogate mothers, and from each other, but they are indistinguishable from the Prop1df/df and Pou1f1dw/dw mice born to mothers from their own backgrounds (Fig. 2, P < 0.001 for comparison of the hearing deficits between Prop1df/df_S and Pou1f1dw/dw_S mutants at both 4 kHz and 20 kHz). Thus, factors intrinsic to the fetus play the major roles in the different responses of Prop1df/df and Pou1f1dw/dw mutant cochlea to hypothyroidism, and maternal effects are minimal in this context.FIG. 2


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)

Gestational and neonatal environments do not account for different hearing abilities of Prop1df and Pou1f1dw mutants. Pups born from surrogate mothers (designated as “Genotype_S”) were tested by ABR. The hearing deficits of Prop1df/df_S and Pou1f1dw/dw_S are significantly different (P < 0.001). For each group, four mice were tested (n = 4).
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Related In: Results  -  Collection

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Fig2: Gestational and neonatal environments do not account for different hearing abilities of Prop1df and Pou1f1dw mutants. Pups born from surrogate mothers (designated as “Genotype_S”) were tested by ABR. The hearing deficits of Prop1df/df_S and Pou1f1dw/dw_S are significantly different (P < 0.001). For each group, four mice were tested (n = 4).
Mentions: To determine the degree to which maternal effects contribute to the different degrees of hearing impairment in Prop1df/df and Pou1f1dw/dw mutants, fertilized eggs with all genotypes from both strains were transplanted into the uteri of B6/D2 surrogate mothers, which would provide common gestation and lactation environments for both mutants. We chose the mothers of the B6/D2 strain as surrogates because they have hybrid vigor and exhibit good mothering instincts. The hearing ability of the progeny born to the surrogates was tested by ABR at 4 weeks of age, including Prop1df/df_S and Pou1f1dw/dw_S mutants as well as wild types from each strain. The hearing deficits of Prop1df/df_S and Pou1f1dw/dw_S mutants are significantly different from their normal littermates, also born to surrogate mothers, and from each other, but they are indistinguishable from the Prop1df/df and Pou1f1dw/dw mice born to mothers from their own backgrounds (Fig. 2, P < 0.001 for comparison of the hearing deficits between Prop1df/df_S and Pou1f1dw/dw_S mutants at both 4 kHz and 20 kHz). Thus, factors intrinsic to the fetus play the major roles in the different responses of Prop1df/df and Pou1f1dw/dw mutant cochlea to hypothyroidism, and maternal effects are minimal in this context.FIG. 2

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