Age-Related Hearing Loss and Degeneration of Cochlear Hair Cells in Mice Lacking Thyroid Hormone Receptor β1

Abstract

A key function of the thyroid hormone receptor β (Thrb) gene is in the development of auditory function. However, the roles of the 2 receptor isoforms, TRβ1 and TRβ2, expressed by the Thrb gene are unclear, and it is unknown whether these isoforms promote the maintenance as well as development of hearing. We investigated the function of TRβ1 in mice with a Thrb(b1) reporter allele that expresses β-galactosidase instead of TRβ1. In the immature cochlea, β-galactosidase was detected in the greater epithelial ridge, sensory hair cells, spiral ligament, and spiral ganglion and in adulthood, at low levels in the hair cells, support cells and root cells of the outer sulcus. Although deletion of all TRβ isoforms causes severe, early-onset deafness, deletion of TRβ1 or TRβ2 individually caused no obvious hearing loss in juvenile mice. However, over subsequent months, TRβ1 deficiency resulted in progressive loss of hearing and loss of hair cells. TRβ1-deficient mice had minimal changes in serum thyroid hormone and thyrotropin levels, indicating that hormonal imbalances were unlikely to cause hearing loss. The results suggest mutually shared roles for TRβ1 and TRβ2 in cochlear development and an unexpected requirement for TRβ1 in the maintenance of hearing in adulthood.

Thyroid Hormone and the Mammalian Auditory System

“…Postnatally, TRβ isoforms are strongly expressed in the greater epithelial ridge (see Sect. 7.1 for description) and weakly in the hair cells and supporting cells of the organ of Corti during late stage differentiation (Bradley et al 1994 ;Ng et al 2015 ) (Fig. 7.3 ).…”

“…TRβ isoforms may substitute for loss of TRα1 but not vice versa because of the more abundant expression of TRβ isoforms in cochlear cell types. Deletion of TRβ2 individually does not cause hearing loss (Abel et al 1999 ;Ng et al 2015 ), suggesting overlap in functions and an ability to compensate between TRβ1 and TRβ2. However, deletion of TRβ1 causes a gradual loss of hearing, suggesting a TRβ1-specifi c role in the long-term maintenance of hearing .…”

Methionine Sulfoxide Reductase A Knockout Mice Show Progressive Hearing Loss and Sensitivity to Acoustic Trauma

“…The loss of cells in the organs of Corti, spiral ganglion, and lateral wall has been reported in hearing loss studies [Fernandez et al, 2015;Hequembourg and Liberman, 2001;Ng et al, 2015]. For this reason, our experiment involved counting spiral ganglion neurons, hair cells, and fibrocytes in the 6-month-old MsrA knockout mice.…”

The actions of thyroid hormone signaling in the nucleus

“…isoforms in the regulation of TSH production by the pituitary [10, 11]. While early studies delineated a unique role for TRβ2 in TSH regulation more recent work suggests that both TRβ isoforms contribute [12, 13]. These isoforms are felt to exert their effect both in the paraventricular nucleus of the hypothalamus to regulate thyrotropin-releasing hormone (TRH) expression and in the pituitary where TSH subunit expression is regulated.…”

“…Interestingly, both TRβ isoforms are important in cochlear development and accordingly hearing development. In adulthood, only the TRβ 1 isoform is required for the maintenance of hearing [10, 13]. The TRβ1 isoform is the principal mediator of TH action in the liver and thus in cholesterol metabolism, while both isoforms have actions in white and brown adipose tissue [17, 18].…”