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Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8
Marija Trajkovic, … , Karl Bauer, Heike Heuer
Marija Trajkovic, … , Karl Bauer, Heike Heuer
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):627-635. https://doi.org/10.1172/JCI28253.
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Research Article Endocrinology Article has an altmetric score of 6

Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8

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Abstract

In humans, inactivating mutations in the gene of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8; SLC16A2) lead to severe forms of psychomotor retardation combined with imbalanced thyroid hormone serum levels. The MCT8-null mice described here, however, developed without overt deficits but also exhibited distorted 3,5,3′-triiodothyronine (T3) and thyroxine (T4) serum levels, resulting in increased hepatic activity of type 1 deiodinase (D1). In the mutants’ brains, entry of T4 was not affected, but uptake of T3 was diminished. Moreover, the T4 and T3 content in the brain of MCT8-null mice was decreased, the activity of D2 was increased, and D3 activity was decreased, indicating the hypothyroid state of this tissue. In the CNS, analysis of T3 target genes revealed that in the mutants, the neuronal T3 uptake was impaired in an area-specific manner, with strongly elevated thyrotropin-releasing hormone transcript levels in the hypothalamic paraventricular nucleus and slightly decreased RC3 mRNA expression in striatal neurons; however, cerebellar Purkinje cells appeared unaffected, since they did not exhibit dendritic outgrowth defects and responded normally to T3 treatment in vitro. In conclusion, the circulating thyroid hormone levels of MCT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected.

Authors

Marija Trajkovic, Theo J. Visser, Jens Mittag, Sigrun Horn, Jan Lukas, Veerle M. Darras, Genadij Raivich, Karl Bauer, Heike Heuer

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Figure 1

Generation and analysis of MCT8-null mice.

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Generation and analysis of MCT8-null mice.
(A) Targeting strategy for th...
(A) Targeting strategy for the MCT8-knockout mouse. As described in Methods, 33 bp of exon 2 were replaced by a lacZ/neomycin reporter cassette. pA, polyadenylation signal; TGA, stop codon. (B) Homologous recombination was confirmed by PCR analysis using 3 primers recognizing the endogenous (E) and the targeted (T) allele as indicated and described in Methods. GS, gene-specific primer; Neo, neomycin cassette–specific primer. (C) Absence of MCT8 protein in MCT8-deficient animals was demonstrated by Western blot analysis of liver homogenates. (D) Deletion of the MCT8 gene was further confirmed by radioactive ISH demonstrating that MCT8 mRNA expression in sagittal brain sections of wild-type animals is completely diminished in sections derived from MCT8-null mice. Deletion of the MCT8 gene was also demonstrated by the expression of lacZ in MCT8–/o animals. CBL, cerebellum; ChP, choroid plexus; CPu, caudate-putamen; CTX, cerebral cortex; DG, dentate gyrus; Hip, hippocampus. Scale bar in D: 1.5 mm. (E) MCT8-null mice develop normally, as indicated by the growth curve. (F) Gait analysis did not reveal any signs of ataxia.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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