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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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Prolonged presence of otoferlin at apical OHCs in Prop1df mutants. A, C Otoferlin immunostaining (red) was done on whole mount preparations of sensory epithelia from the apical turn of Prop1df mutants and wild type. B, D Frozen sections of organ of Corti were collected and stained by anti-Otoferlin antibody (red). Arrowheads indicate the rows of OHCs. Arrows point to the IHCs. Nuclei are blue in all stainings.
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Fig6: Prolonged presence of otoferlin at apical OHCs in Prop1df mutants. A, C Otoferlin immunostaining (red) was done on whole mount preparations of sensory epithelia from the apical turn of Prop1df mutants and wild type. B, D Frozen sections of organ of Corti were collected and stained by anti-Otoferlin antibody (red). Arrowheads indicate the rows of OHCs. Arrows point to the IHCs. Nuclei are blue in all stainings.

Mentions: Otoferlin is thought to be the major calcium sensor and essential for exocytosis at both inner hair cell (IHC) and immature OHC ribbon synapses (Roux et al. 2006; Beurg et al. 2008). Expression of otoferlin begins prenatally in both IHCs and OHCs and vanishes from OHCs by P6 (Roux et al. 2006). The disappearance of otoferlin immunostaining in OHCs occurs around the same time as the retraction of afferent fibers from OHCs (Beurg et al. 2008). Together with myosin VI, otoferlin is involved in the maintenance of the basolateral synaptic structure of IHCs (Heidrych et al. 2009; Roux et al. 2009). We examined the expression of otoferlin by immunostaining whole-mount and cryosectioned tissues. Similar expression levels of otoferlin were seen in IHCs of Prop1df/df mutant cochlea as the wild type. Abnormally strong otoferlin immunostaining persists in the OHCs in the apical coil of 6-week-old Prop1df/df mutant cochlea (Fig. 6C, D) and none was observed in the wild-type littermates. Weak otoferlin immunostaining is reported in the OHCs in the apical region of mature cochlea in wild-type animals (Roux et al. 2006), but this may represent a strain difference in maturation or sensitivity of detection. Nevertheless, the abnormal persistence of otoferlin expression in apical OHCs of Prop1df/df mutant cochlea may represent some remaining immaturity of the cells.FIG. 6


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)

Prolonged presence of otoferlin at apical OHCs in Prop1df mutants. A, C Otoferlin immunostaining (red) was done on whole mount preparations of sensory epithelia from the apical turn of Prop1df mutants and wild type. B, D Frozen sections of organ of Corti were collected and stained by anti-Otoferlin antibody (red). Arrowheads indicate the rows of OHCs. Arrows point to the IHCs. Nuclei are blue in all stainings.
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Related In: Results  -  Collection

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Fig6: Prolonged presence of otoferlin at apical OHCs in Prop1df mutants. A, C Otoferlin immunostaining (red) was done on whole mount preparations of sensory epithelia from the apical turn of Prop1df mutants and wild type. B, D Frozen sections of organ of Corti were collected and stained by anti-Otoferlin antibody (red). Arrowheads indicate the rows of OHCs. Arrows point to the IHCs. Nuclei are blue in all stainings.
Mentions: Otoferlin is thought to be the major calcium sensor and essential for exocytosis at both inner hair cell (IHC) and immature OHC ribbon synapses (Roux et al. 2006; Beurg et al. 2008). Expression of otoferlin begins prenatally in both IHCs and OHCs and vanishes from OHCs by P6 (Roux et al. 2006). The disappearance of otoferlin immunostaining in OHCs occurs around the same time as the retraction of afferent fibers from OHCs (Beurg et al. 2008). Together with myosin VI, otoferlin is involved in the maintenance of the basolateral synaptic structure of IHCs (Heidrych et al. 2009; Roux et al. 2009). We examined the expression of otoferlin by immunostaining whole-mount and cryosectioned tissues. Similar expression levels of otoferlin were seen in IHCs of Prop1df/df mutant cochlea as the wild type. Abnormally strong otoferlin immunostaining persists in the OHCs in the apical coil of 6-week-old Prop1df/df mutant cochlea (Fig. 6C, D) and none was observed in the wild-type littermates. Weak otoferlin immunostaining is reported in the OHCs in the apical region of mature cochlea in wild-type animals (Roux et al. 2006), but this may represent a strain difference in maturation or sensitivity of detection. Nevertheless, the abnormal persistence of otoferlin expression in apical OHCs of Prop1df/df mutant cochlea may represent some remaining immaturity of the cells.FIG. 6

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