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N E W S A N D V I E W S Hear, Hear! Thyroid Hormone Transporters in Cochlear Development Heike Heuer Leibniz Institute for Age Research/Fritz Lipmann Institute, D-07745 Jena, Germany earing 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 complex process of cochlea differentiation, 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 H 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- ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/en.2011-1722 Received September 6, 2011. Accepted September 27, 2011. Abbreviations: CNS, Central nervous system; Dio2, type 2 deiodinase; Dio3, type 3 deiodinase; Mct8, monocarboxylate transporter 8; Oatp1c1, organic anion transporting polypeptide-1c1; TH, thyroid hormone; TR, TH receptor. For article see page 5053 4478 endo.endojournals.org Endocrinology, December 2011, 152(12):4478 – 4480 Endocrinology, December 2011, 152(12):4478 – 4480 icantly to TH uptake and efflux in the brain as well, although their in vivo relevance has yet not been extensively elucidated (18 –20). Defining the exact routes of TH traffic in the CNS as well as in cochlea is hampered by the fact that in both organs, the cells that are most sensitive to T3 are not in direct contact with the blood flow. As another complication, these T3-consuming cells are not identical to the T3-generating cells that express Dio2. In the brain, Dio2 is localized in astrocytes and tanycytes, whereas in the cochlea, Dio2 is expressed in fibrocytes in close proximity to blood vessels (1, 7, 21, 22). Recent studies in the rodent brain and in human cells have provided direct evidence that T3 generated by Dio2 in glial cells can activate neuronal TR, thereby acting in a paracrine manner (23). Based on the differential localization of Dio2 and TR, it is more than tempting to envisage a similar mode of T3 signaling in the cochlea that in turn requires the presence of TH transporters in the T3-generating as well as in the T3responsive cells. In their comprehensive study, Sharlin and co-workers (1) determined the cellular expression pattern of the TH transporter candidates Mct8, Mct10, Oapt1c1, Lat1, and Lat2 during different stages of mouse cochlear development by in situ hybridization and immunofluorescence analysis. They observed a very restricted expression pattern for Oatp1c1 localized in Dio2-expressing fibrocytes where it may facilitate the cellular entry of T4. Lat1 in turn may be involved in the uptake of TH from the circulation because it is strongly expressed in cochlear blood vessels. Mct8 is the only TH transporter present in the greater epithelial ridge and shows an overlapping expression with Oatp1c1 in the tympanic border cells underlying the sensory epithelium. Mct8 is also localized to spiral ganglion neurons, thereby showing overall an overlapping expression with TR, the predominant TR in the cochlea. Finally, Mct10 exhibited the most restricted expression pattern of all the transporters under investigation and was found only in specialized cells in the outer sulcus. Although the cellular expression data the authors present are purely descriptive, they provide an important conceptual basis of how TH trafficking may take place in the developing cochlea (Fig. 1). Studies using TH transporter-deficient mice will certainly challenge these hypotheses and may even result in the identification of additional candidates involved in the network of TH transporters acting in the auditory system. Finally, in light of the crucial role of TH in regulating retinal photoreceptor development, it appears worthwhile to determine the TH transporter expression pattern in the developing mouse visual system as well (24 –26). endo.endojournals.org 4479 FIG. 1. Schematic drawing of a hypothetical and simplified model of TH metabolism and action in the developing mouse cochlea. T4 may be transported via Lat1 across the capillary endothelial cells and then enters fibrocytes via Oatp1c1. After the conversion of T4 to T3 by Dio2, T3 may be exported via Mct8 to enter then the TR-expressing target cells via Mct8, Lat1, and Mct10. Premature activation of TR receptors by T3 is prevented by the presence of Dio3 that can inactivate T3 to its inactive metabolite 3,3⬘-diiodothyronine (T2). Can we draw any conclusions from these mouse data with regard to TH transporters in the human auditory system? Comparison of the mouse and human TH transporter repertoire already revealed striking differences with transporters present in the mouse but not in the human genome (27). Even the distribution pattern of orthologs appears to vary significantly between mice and men as it has been shown, e.g. for Lat2 and Oatp1c1 in the CNS (19, 28). However, as Sharlin et al. (1) discuss, both MCT8 and OAT1C1 appear to be present in the human cochlea. Moreover, the human OATP1C1 gene is associated with a deafness locus on chromosome 12, suggesting that mutations in this TH transporter gene may lead to severe hearing impairments (29). Currently, the search is still on for patients with hearing deficits carrying mutations in TH transporter genes. Acknowledgments Address all correspondence and requests for reprints to: Heike Heuer, Ph.D., Leibniz Institute for Age Research/Fritz Lipmann Institute e.V., Beutenbergstrasse 11, D-07745 Jena, Germany. E-mail: [email protected]. Disclosure Summary: The author has nothing to disclose. 4480 Heuer News & Views Endocrinology, December 2011, 152(12):4478 – 4480 References 1. Sharlin DS, Visser TJ, Forrest D 2011 Developmental and cell-specific expression of thyroid hormone transporters in the mouse cochlea. Endocrinology 152:5053–5064 2. DeLong GR, Stanbury JB, Fierro-Benitez R 1985 Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). 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