A Protective Role for Type 3 Deiodinase, a Thyroid Hormone-Inactivating Enzyme, in Cochlear Development and Auditory Function

Abstract

Thyroid hormone is necessary for cochlear development and auditory function, but the factors that control these processes are poorly understood. Previous evidence indicated that in mice, the serum supply of thyroid hormone is augmented within the cochlea itself by type 2 deiodinase, which amplifies the level of T(3), the active form of thyroid hormone, before the onset of hearing. We now report that type 3 deiodinase, a thyroid hormone-inactivating enzyme encoded by Dio3, is expressed in the immature cochlea before type 2 deiodinase. Dio3-/- mice display auditory deficits and accelerated cochlear differentiation, contrasting with the retardation caused by deletion of type 2 deiodinase. The Dio3 mRNA expression pattern in the greater epithelial ridge, stria vascularis, and spiral ganglion partly overlaps with that of thyroid hormone receptor beta (TRbeta), the T(3) receptor that is primarily responsible for auditory development. The proposal that type 3 deiodinase prevents premature stimulation of TRbeta was supported by deleting TRbeta, which converted the Dio3-/- cochlear phenotype from one of accelerated to one of delayed differentiation. The results indicate a protective role for type 3 deiodinase in hearing. The auditory system illustrates the considerable extent to which tissues can autoregulate their developmental response to thyroid hormone through both type 2 and 3 deiodinases.

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

“…Thus, TH signaling-mediated regulation of cone viability appears to be independent of TH regulation of cone opsin expression. This view is also supported by the following: (i) Stimulating TH signaling induces death of rods, which do not express cone opsin; (ii) high TH signaling causes auditory deficits and cochlear degeneration (13); and (iii) high TH signaling induces death of other cell types, including cancer cells (14-17), which do not express opsins.…”

“…Triiodothyronine (T3) treatment was shown to cause cone death in mice and this effect was reversed by deletion of TRβ2 gene (12). Excessive TH signaling was also shown to induce auditory defects and cochlear degeneration in mice (13). TH signaling has been associated with apoptosis of a variety of human cell lines, including lymphocytes (14), breast cancer cells (15), HeLa cells (16), and pituitary tumor cells (17), and TH signaling has been well documented in apoptotic tissue remodeling during anuran metamorphosis (18,19).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…This is also observed in animal models of transgenic Dio2 expression in the heart (273,274). In contrast, D3 inactivation results in localized increase in thyroid hormone signaling as evidenced in the D3 KO mouse (64,239,(275)(276)(277)(278)(279).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Early in development, D3 is expressed in the immature cochlea. If D3 is absent, such as in D3KO mice, the premature exposure to inappropriate T3 levels accelerates cochlear differentiation resulting in an auditory deficit (40). Additionally, in early postnatal life, a sharp focal burst of D2 activity in the cochlear precursors is also required to provide the proper amount of T3 for the final development of normal hearing (41).…”