Hear, Hear! Thyroid Hormone Transporters in Cochlear Development

Abstract

Hearing is one of the most sensitive functions controlled by thyroid hormone (TH). It therefore appears to be of utmost importance to define the transporters that mediate TH passage within the auditory system because mutations in specific TH transporter genes may be connected to pathological findings. In this issue of Endocrinology, Sharlin et al. (1) provide detailed information on the temporal and spatial expression pattern of several TH transporter candidates in the mouse cochlea where these transporters may act as decisive gatekeepers. These data not only enlarge our understanding about TH traffic and action in the hearing system but also establish a sound basis for further studies such as the analysis of TH transporter-deficient mice. The development of hearing in humans as well as in rodents is highly dependent on sufficient TH supply. TH deprivation particularly during late fetal and neonatal stages can result in hearing impairments or even in deafness if TH substitution is not instituted within a critical time window (2, 3). Consequently, hearing impairment is common in geographic areas with a prevalence of iodine deficiency and is also evident in various forms of thyroid disorders such as congenital hypothyroidism (4) or resistance to TH (5, 6). A major target of TH in the auditory system is the cochlea where TH promotes the terminal differentiation of a variety of cell types. In particular, TH regulates the remodeling of the greater epithelial ridge and the tectorial membrane as well as the differentiation of the sensory epithelium that contains the sound-transducing hair cells. During this complexprocessof cochleadifferentiation, the amount of T3 as the receptor active form of TH is intriguingly tightly regulated by the type 2 deiodinase (Dio2) and type 3 deiodinase (Dio3) (7). The latter enzyme, which inactivates T4 and T3 by inner ring deiodination, is predominantly expressed at late prenatal stages and is thought to prevent a premature stimulation of TH receptors (TR). Consequently, Dio3 knockout mice display an accelerated cochlea differentiation and auditory defects (8). In contrast, Dio2 exhibits outer ring deiodinase activity and is responsible for converting T4 to T3. The postnatal rise in Dio2 activity with a peak at d 7 leads to an amplification of the cochlear T3 levels particularly during the time period when the differentiation of the auditory system is most dependent on sufficient T3 supply (7). Accordingly, Dio2 knockout mice suffer from hearing loss as well, but in contrast to Dio3 / mice, they show a retarded cochlear development (9). In light of these findings, it appears not too surprising that mouse mutants deficient in TR display severe cochlear defects as well (10, 11). Another mechanism by which the amount of T3 can be locally controlled is a differential expression of TH transporters. Studies in mouse mutants have revealed that the inactivation of the TH transporter monocarboxylate transporter 8 [Mct8 (Slc16a2)] results in an impaired transport of T3 via the blood-brain barrier and, consequently, in a hypothyroid situation in the central nervous system (CNS) (12–14). Patients with inactivating mutations in the X-linked MCT8 gene suffer from a severe form of psychomotor retardation and neurological impairments indicating that the human brain may even be more dependent on MCT8 for mediating TH entry into the brain than the mouse CNS (15–17). Other transporters such as the organic anion transporting polypeptide-1c1 [Oatp1c1 (Slco1c1)], the monocarboxylate transporter Mct10 (Slc16a10), or the L-type amino acid transporters Lat1 (Slc7a5) and Lat2 (Slc7a8) have been discussed to contribute signif-