Abstract
Thyroid hormones (THs; T3 and T4) enter cells using specific transporters and regulate development and metabolism. Mutation in the TH transporter monocarboxylate transporter 8 (MCT8, SLC16A2) is associated with brain hypothyroidism and neurological impairment. We established mct8 mutant (mct8−/−) zebrafish as a model for MCT8 deficiency, which causes endocrinological, neurological, and behavioral alterations. Here, we profiled the transcriptome of mct8−/− larvae. Among hundreds of differentially expressed genes, the expression of a cluster of vision-related genes was distinct. Specifically, the expression of the opsin 1 medium wave sensitive 2 (opn1mw2) decreased in two mct8 mutants: mct8−/− and mct8−25bp−/− larvae, and under pharmacological inhibition of TH production. Optokinetic reflex (OKR) assays showed a reduction in the number of conjugated eye movements, and live imaging of genetically encoded Ca2+ indicator revealed altered neuronal activity in the pretectum area of mct8−25bp−/− larvae. These results imply that MCT8 and THs regulate the development of the visual system and suggest a mechanism to the deficiencies observed in the visual system of MCT8-deficiency patients.
Highlights
Insufficient production of the thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), and altered TH transport into the cells during prenatal and postnatal periods causes profound neurodevelopmental disorders [1,2]
In human organoids, THs regulate photoreceptor subtype specification [14]. These findings suggest that abnormal cellular transport of THs can affect the expression and function of opsins and the development of the visual system in monocarboxylate transporter 8 (MCT8) deficiency
The analysis identified 97 and 204 up-regulated (Table S1) and down-regulated (Table S2) genes, respectively, in mct8−/− larvae (Figure 1A)
Summary
Insufficient production of the thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), and altered TH transport into the cells during prenatal and postnatal periods causes profound neurodevelopmental disorders [1,2]. THs primarily regulate terminal neuronal differentiation processes, such as dendritic and axonal growth, synaptogenesis, cell migration, and myelination [3,4]. Several transmembrane TH transporters have been functionally described, including the monocarboxylate transporter 8. The critical role of MCT8 in regulating TH signaling, metabolism, and brain development is evident by the symptoms of the X-linked inherited Allan–Herndon–. Dudley syndrome (AHDS/MCT8-deficiency) associated with mutations in the MCT8. MCT8-deficiency is characterized by severe cognitive deficits, spastic quadriplegia, hypotonia, and elevated serum T3 levels [7,8]. Abnormal conjugating eye movements and strabismus were diagnosed in the patients [6,8,9], suggesting an altered visuomotor function in MCT8-deficient patients
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