Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss

König, Ovidiu; Rüttiger, Lukas; Müller, Marcus; Zimmermann, Ulrike; Erdmann, Bettina; Kalbacher, Hubert; Gross, Manfred; Knipper, Marlies

doi:10.1096/fj.07-9171com

Cited by 41 publications

(35 citation statements)

References 58 publications

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“…Megalin could therefore possibly be a candidate for binding of estrogen or ERs. This could indicate degenerative pathways in the inner ear where loss of estrogen transport could be detrimental (König et al 2008). Based on the findings of König et al, the hearing loss in the ER-b K/K mice in the present study could be explained by abnormal water/ion regulation caused by pre-mature degeneration of ER-b-deficient stria vascularis.…”

Section: Discussionsupporting

confidence: 65%

“…Additional factors may operate in the degeneration of structures in the inner ear of ER-b K/K mice. König et al (2008) reported that megalin, a low-density lipoprotein receptor, is present in the same cells (marginal cells) in stria vascularis as ER-b. FITC-labeled estrogen is taken up into the strial marginal cells; however, in megalin-deficient mice the uptake of FITC-labeled estrogen into strial marginal cells is reduced.…”

Section: Discussionmentioning

confidence: 99%

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Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

Simonoska¹,

Stenberg²,

Duan

et al. 2009

Journal of Endocrinology

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There are well known differences between males and females in hearing. In the present study, the role of estrogen receptor-b (ER-b; listed as ESR2 in the MGI Database) in hearing was investigated by comparing hearing and morphology of the inner ear in ER-b knock-out mice (ER-b) with that of wild-type (WT) littermates. Hearing was analyzed with auditory brainstem response audiometry at 3 and 12 months. The ER-b K/K mice were deaf at 1 year of age, and the morphological analysis showed absence of hair cells and loss of the whole organ of Corti initiated in the basal turn of the cochlea. Furthermore, in ER-b, but not in WT mice, the spiral ganglion was lacking many of its neurons.Immunostaining showed the presence of both ER-a (listed as ESR1 in the MGI Database) and ER-b in the nuclei of some neurons in the inner ear in WT mice, but no ER-b was found in the ER-b K/K mice as expected. ER-a staining was predominant in the nuclei of large neurons and ER-b in nuclei of small neurons and fibroblasts. These results reveal that both ERs are present in the inner ear at specific localizations suggesting subtype-specific functions. It is concluded that ER-b is important for the prevention of agerelated hearing loss. These findings strengthen the hypothesis that estrogen has a direct effect on hearing functions.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

Simonoska¹,

Stenberg²,

Duan

et al. 2009

Journal of Endocrinology

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“…Whether these carriers are ligands to megalin remains to be shown, once the identities of such carriers have been revealed. Recently, megalin-dependent uptake of fluorescentlabeled estradiol into the marginal cells of the stria vascularis in the inner ear has been shown (Konig et al, 2008). This finding strongly supports a role for the receptor as cellular entry pathway for sex steroids in vivo.…”

mentioning

confidence: 54%

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Willnow

Nykjaer

2010

Molecular and Cellular Endocrinology

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Steroid hormones are believed to enter cells solely by free diffusion through the plasma membrane. However, recent studies suggest the existence of cellular uptake pathways for carrier-bound steroids. Similar to the clearance of cholesterol via lipoproteins, these pathways involve the recognition of carrier proteins by endocytic receptors on the surface of target cells, followed by internalization and cellular delivery of the bound sterols. Here, we discuss the emerging concept that steroid hormones can selectively enter steroidogenic tissues by receptor-mediated endocytosis; and we discuss the implications of these uptake pathways for steroid hormone metabolism and action in vivo.

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“…1D,F,G,I). Mouse Lrp2 mutants suffer from progressive hearing loss associated with defects in the stria vascularis (Konig et al, 2008), but the reported malformations do not resemble the N-myc mutant phenotype. Ecel1 homozygous mouse mutants die at birth or soon after as a result of respiratory distress but no inner ear phenotype has so far been documented (Schweizer et al, 1999).…”

Section: Resultsmentioning

confidence: 98%

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

et al. 2015

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Transcriptional regulatory networks are essential during the formation and differentiation of organs. The transcription factor N-myc is required for proper morphogenesis of the cochlea and to control correct patterning of the organ of Corti. We show here that the Otx2 gene, a mammalian ortholog of the Drosophila orthodenticle homeobox gene, is a crucial target of N-myc during inner ear development. Otx2 expression is lost in N-myc mouse mutants, and N-myc misexpression in the chick inner ear leads to ectopic expression of Otx2. Furthermore, Otx2 enhancer activity is increased by N-myc misexpression, indicating that N-myc may directly regulate Otx2. Inactivation of Otx2 in the mouse inner ear leads to ectopic expression of prosensory markers in non-sensory regions of the cochlear duct. Upon further differentiation, these domains give rise to an ectopic organ of Corti, together with the respecification of non-sensory areas into sensory epithelia, and the loss of Reissner's membrane. Therefore, the Otx2-positive domain of the cochlear duct shows a striking competence to develop into a mirrorimage copy of the organ of Corti. Taken together, these data show that Otx2 acts downstream of N-myc and is essential for patterning and spatial restriction of the sensory domain of the mammalian cochlea.

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Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss

Cited by 41 publications

References 58 publications

Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Otx2 is a target of N-myc and acts as a suppressor of sensory development in the mammalian cochlea

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