Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking <i>Slc26a4</i>/pendrin expression

Wangemann, Philine; Kim, Hyoung-Mi; Billings, Sara E.; Nakaya, Kazuhiro; Li, Xiangming; Singh, Ruchira; Sharlin, David S.; Forrest, Douglas; Marcus, Daniel C.; Fong, Peter

doi:10.1152/ajprenal.00011.2009

Cited by 62 publications

(68 citation statements)

References 64 publications

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“…I -is a known in vitro exchange substrate of pendrin (25), and its concentration probably rises soon following the onset of type 2 deiodinase activity in the late embryonic cochlea (26). Cochlear concentrations and mechanism of I -homeostasis are unknown but, if there were not a mechanism to disperse I -, an excess could conceivably exert a toxic effect on cells within the cochlea, inhibit deiodinase reaction(s) leading to cochlear hypothyroidism (27), or produce a combination of these effects. Finally, the dependence of renal Na + reabsorption on luminal HCO 3 -secretion and alkalinization by pendrin (28) raises the possibility of an analogous role in embryonic endolymph.…”

Section: Discussionmentioning

confidence: 99%

Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition

Choi¹,

Kim²,

Ito³

et al. 2011

J. Clin. Invest.

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115

137

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Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO 3 -into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pendrin was derived from the transgenes. Varying the temporal expression of Slc26a4 revealed that E16.5 to P2 was the critical interval in which pendrin was required for acquisition of normal hearing. Lack of pendrin during this period led to endolymphatic acidification, loss of the endocochlear potential, and failure to acquire normal hearing. Doxycycline initiation at E18.5 or discontinuation at E17.5 resulted in partial hearing loss approximating the human EVA auditory phenotype. These data collectively provide mechanistic insight into hearing loss caused by SLC26A4 mutations and establish a model for further studies of EVA-associated hearing loss.

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Section: Discussionmentioning

confidence: 99%

Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition

Choi¹,

Kim²,

Ito³

et al. 2011

J. Clin. Invest.

Self Cite

115

137

View full text Add to dashboard Cite

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“…Pendrin has been proposed as the protein mediating the step of iodide export from the cell into the follicular lumen, i.e., of iodide crossing the thyrocyte's apical membrane (3). However, several arguments indicate that pendrin is not critical for this transport (38,44) as mice deficient for pendrin are euthyroid (4,6,42) and patients affected by the Pendred syndrome, i.e., homozygotic pendrin inactivation, may develop goiters in iodine-deficient conditions but usually not before the second decade of life (3). Another pathway for iodide transport across the apical membrane must therefore be considered, and the definition of its identity and hormonal responsiveness constitutes the aim of the present study.…”

mentioning

confidence: 99%

Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte

Twyffels

Strickaert

Virreira

et al. 2014

American Journal of Physiology-Cell Physiology

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Iodide is captured by thyrocytes through the Na ϩ /I Ϫ symporter (NIS) before being released into the follicular lumen, where it is oxidized and incorporated into thyroglobulin for the production of thyroid hormones. Several reports point to pendrin as a candidate protein for iodide export from thyroid cells into the follicular lumen. Here, we show that a recently discovered Ca 2ϩ -activated anion channel, TMEM16A or anoctamin-1 (ANO1), also exports iodide from rat thyroid cell lines and from HEK 293T cells expressing human NIS and ANO1. The Ano1 mRNA is expressed in PCCl3 and FRTL-5 rat thyroid cell lines, and this expression is stimulated by thyrotropin (TSH) in rat in vivo, leading to the accumulation of the ANO1 protein at the apical membrane of thyroid follicles. Moreover, ANO1 properties, i.e., activation by intracellular calcium (i.e., by ionomycin or by ATP), low but positive affinity for pertechnetate, and nonrequirement for chloride, better fit with the iodide release characteristics of PCCl3 and FRTL-5 rat thyroid cell lines than the dissimilar properties of pendrin. Most importantly, iodide release by PCCl3 and FRTL-5 cells is efficiently blocked by T16A inh-A01, an ANO1-specific inhibitor, and upon ANO1 knockdown by RNA interference. Finally, we show that the T16A inh-A01 inhibitor efficiently blocks ATP-induced iodide efflux from in vitro-cultured human thyrocytes. In conclusion, our data strongly suggest that ANO1 is responsible for most of the iodide efflux across the apical membrane of thyroid cells.anoctamin-1; iodide release; pendrin; thyrocyte; TMEM16A

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“…Pendred syndrome, an autosomal recessive disorder, is mainly characterized by deafness, but some patients also present with hypothyroidism (63). No thyroid phenotype has been reported for Slc26a4 KO mice (64), suggesting that pendrin plays a non-essential role in iodide transport, at least in the mouse, and that alternate transporters, most likely the Ca 2+ -activated ion channel Anoctamin-1, can mediate apical iodide efflux (1,2). Using Thyr-IL-4 transgenic mice, this study showed for the first time an IL-4-dependent induction of Slc26a4 transcription, which was associated with increased apical expression of pendrin.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Interleukin-4 in the Thyroid of Transgenic Mice Upregulates the Expression ofDuox1and the Anion Transporter Pendrin

Eskalli

Achouri

Hahn

et al. 2016

Thyroid

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Background:The dual oxidases (Duox) are involved in hydrogen peroxide generation, which is essential for thyroid hormone synthesis, and therefore they are markers of thyroid function. During inflammation, cytokines upregulate DUOX gene expression in the airway and the intestine, suggesting a role for these proteins in innate immunity. It was previously demonstrated that interleukin-4 (IL-4) upregulates DUOX gene expression in thyrocytes. Although the role of IL-4 in autoimmune thyroid diseases has been studied extensively, the effects of IL-4 on thyroid physiology remain largely unknown. Therefore, a new animal model was generated to study the impact of IL-4 on thyroid function. Methods: Transgenic (Thyr-IL-4) mice with thyroid-targeted expression of murine IL-4 were generated. Transgene expression was verified at the mRNA and protein level in thyroid tissues and primary cultures. The phenotype of the Thyr-IL-4 animals was characterized by measuring serum thyroxine (T4) and thyrotropin levels and performing thyroid morphometric analysis, immunohistochemistry, whole transcriptome sequencing, quantitative reverse transcription polymerase chain reaction, and ex vivo thyroid function assays. Results: Thyrocytes from two Thyr-IL-4 mouse lines (#30 and #52) expressed IL-4, which was secreted into the extracellular space. Although 10-month-old transgenic animals had T4 and thyrotropin serum levels in the normal range, they had altered thyroid follicular structure with enlarged follicles composed of elongated thyrocytes containing numerous endocytic vesicles. These follicles were positive for T4 staining the colloid, indicating their capacity to produce thyroid hormones. RNA profiling of Thyr-IL-4 thyroid samples revealed modulation of multiple genes involved in inflammation, while no major leukocyte infiltration could be detected. Upregulated expression of Duox1, Duoxa1, and the pendrin anion exchanger gene (Slc26a4) was detected. In contrast, the iodide symporter gene Slc5a5 was markedly downregulated resulting in impaired iodide uptake and reduced thyroid hormone levels in transgenic thyroid tissue. Hydrogen peroxide production was increased in Thyr-IL-4 thyroid tissue compared with wild-type animals, but no significant oxidative stress could be detected. Conclusions: This is the first study to show that ectopic expression of IL-4 in thyroid tissue upregulates Duox1/ Duoxa1 and Slc26a4 expression in the thyroid. The present data demonstrate that IL-4 could affect thyroid morphology and function, mainly by downregulating Slc5a5 expression, while maintaining a normal euthyroid phenotype.

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Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression

Abstract: P. Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression.

Cited by 62 publications

References 64 publications

Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition

Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition

Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte

Overexpression of Interleukin-4 in the Thyroid of Transgenic Mice Upregulates the Expression ofDuox1and the Anion Transporter Pendrin

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