Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing

Abstract

Thyroid hormone signaling during a postnatal period in the mouse is essential for cochlear development and the subsequent onset of hearing. To study the control of this temporal dependency, we investigated the role of iodothyronine deiodinases, which in target tissues convert the prohormone thyroxine into triiodothyronine (T3), the active ligand for the thyroid hormone receptor (TR). Type 2 5 -deiodinase (D2) activity rose dramatically in the mouse cochlea to peak around postnatal day 7 (P7), after which activity declined by P10. This activity peak a few days before the onset of hearing suggests a role for D2 in amplifying local T3 levels at a critical stage of cochlear development. A mouse cochlear D2 cDNA was isolated and demonstrated near identity to rat D2. In situ hybridization localized D2 mRNA in periosteal connective tissue in the modiolus, the cochlear outer capsule and the septal divisions between the turns of the cochlea. Surprisingly, D2 expression in these regions that give rise to the bony labyrinth was complementary to TR expression in the sensory epithelium. Thus, the connective tissue may control deiodination of thyroxine and release of T3 to confer a paracrine-like control of TR activation. These results suggest that temporal and spatial control of ligand availability conferred by D2 provides an unexpectedly important level of regulation of the TR pathways required for cochlear maturation.development ͉ thyroid hormone receptor ͉ deiodinase ͉ cochlea O ne of the most sensitive functions controlled by thyroid hormone (TH) is the development of hearing, as is evident from the deafness associated with human congenital hypothyroidism. Experimental hypothyroidism in rodents has revealed that the cochlea is a major site of TH action and has shown that cochlear maturation and the onset of auditory function around postnatal day 14 (P14) require TH during a critical period between the late embryonic stage and the second postnatal week (1-3). This developmental window is strictly delineated, because TH can rescue cochlear morphogenesis and auditory function in hypothyroid mice or rats if provided during early postnatal stages but not after P10-P12. Little is known of the mechanisms that control this temporal regulation.TH receptors (TR) play a critical role in the auditory system (4). TR␣1 and TR␤, encoded by two related genes, are nuclear receptors that act as ligand-dependent transcription factors (5, 6). TR␣1 and TR␤ are expressed in the cochlea with TR␤ mRNA being prominent both in the embryonic otic vesicle and in the postnatal sensory epithelium and spiral ganglion (7-9). TR␤-deficient mice and humans are severely deaf, as assessed by defective auditory-evoked brainstem responses (10, 11), whereas TR␣1-deficient mice have a normal auditory-evoked brainstem response (12). Mild hearing defects occur in Ϸ20% of cases of the human syndrome of resistance to thyroid hormone, which is associated with TR␤ point mutations (13).The control of ligand availability in target tissues constitutes another level of ...

Thyroid hormone is a critical determinant for the regulation of the cochlear motor protein prestin

“…This phenomenon might be attributed either to transcription factors (25) or local compensation of T3 levels by type 2 deiodinase (38). The absence of TH for more than 3 weeks, however, still was associated with an immature prestin protein distribution across the entire plasma membrane.…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…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). This spike is missing in D2KO mice leading again to severe hearing impairment, and this deficit can be prevented by the properly timed administration of T3 to the mother (42).…”

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

“…Protocols for in situ hybridization and IHC have been described (445,(480)(481)(482)(483)(484). These may be performed on paraffin-embedded sections or fixed frozen tissue if preservation of detailed histological architecture is of significant importance (485). However, paraffin embedding interferes with RNA quality, thus better signal-to-noise ratio and analysis of gene expression are obtained using fixed frozen tissue.…”