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Departments of Medicine (A.M.D., X.-H.L., R.E.W., S.R.), Human Genetics (K.M.), Pediatrics and Committee on Genetics (S.R.), University of Chicago, Chicago, Illinois 60637
Address all correspondence and requests for reprints to: Samuel Refetoff, University of Chicago, MC 3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}uchicago.edu.
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Introduction |
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Until recently, the physiological role of TH membrane transporters has remained elusive. The identification of patients with mutations in the X-linked TH transporter, monocarboxylate transporter 8 (MCT8), has revealed the role played by this transmembrane carrier in the intracellular availability of TH. Hemizygous MCT8-deficient males present a syndrome with two components: a thyroid defect (increased total and free serum T3 and decreased total and free T4 and rT3 concentrations) and severe psychomotor and developmental delay (generalized dystonia combined with spasticity, mental retardation, lack of verbal communication, poor head control and coordination) (6, 7, 8, 9, 10). As is the case for most X-linked diseases, males are more severely affected in terms of both the neurological and thyroid defects (6, 7, 8, 9, 10), whereas female carriers have only mild thyroid function test (TFT) abnormalities (6, 7, 8, 9, 10). In the last year, MCT8 gene mutations have been found to be the cause of Allan-Herndon-Dudley syndrome (9, 10), an X-linked syndromic form of mental retardation first described in 1944 (11) (Online Mendelian Inheritance in Man access no. OMIM 309600).
Understanding the mechanism producing the TFT abnormalities caused by MCT8 mutations in humans has proved challenging. The presentation is not typical of hypothyroidism (12, 13). Investigations in humans are limited by the accessibility of tissues and by the patients’ disability, rendering a mouse model mandatory for the study of this syndrome. We therefore generated a mouse deficient in Mct8 through homologous recombination in embryonic stem (ES) cells. The resulting Mct8 knockout male (Mct8–/y) mice replicate the human thyroid phenotype. Our findings from in vivo and in vitro studies in male Mct8–/y mice indicate that Mct8-dependent tissues, such as the cerebrum, are TH deficient in the absence of Mct8. Tissues expressing other TH transporters, such as the liver, are thyrotoxic. This tissue-specific TH availability allows for the coexistence of increased deiodinase 1 (D1) and increased deiodinase 2 (D2) enzymatic activities stimulated by opposite states of intracellular TH availability, further aggravating the status of increased 5'-deiodination unbalanced by 5-deiodination. We conclude that these tissue-specific differences in intracellular TH content are responsible for the unusual clinical presentation of this defect.
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Materials and Methods |
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Targeting construct
Isogenic genomic DNA (gDNA) from the E14Tg1A.4 129P2 ES male feederless ES cell line was used to amplify the homology arms by long-range PCR using a mixture of 1/10 Pfu Turbo polymerase (Stratagene, La Jolla, CA) and 9/10 LA Taq Polymerase (Takara, Kyoto, Japan). All PCR fragments were cloned into pGEM-T-easy (Promega, Madison, WI) and sequenced. Fragments were then cloned into pBluescript used as the backbone vector for the final targeting construct. The components of the final targeting vector are shown in Fig. 1A
. The diphtheria toxin A (DTA) cassette was excised from the pPGKneoDTA vector (from Dr. Soriano) and the ACN cassette from plasmid pACN (Dr. Capecchi). The final construct was confirmed by restriction digestions and sequencing. Targeting construct linearized with SacII (25 µg) was electroporated into the feeder-independent E14Tg2A.4 129P2-derived ES cells. After selection with G418 (200 µg/ml), 307 neomycin-resistant colonies were screened by Southern blot with outside probes, a 5' probe in exon 2 and a 3' probe in exon 5 of mouse Mct8 (Fig. 1B).
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). Mct8–/y males were generated in F2 C57Bl/6J backcross in expected Mendelian ratios (see Results). Genotyping of mice was performed using a common forward primer and wild-type (WT) and null allele-specific reverse primers (Fig. 1D) (sequences available upon request). For most analyses presented here, we have assessed F2 C57Bl/6J:129Sv mixed genetic background mice. Inbred 129Sv Mct8–/y mice were obtained as pups of the F1 Mct8–/+ females generated by breeding the transmitting male chimeras with 129Sv WT females (stock no. 002448; The Jackson Laboratory, Bar Harbor, ME).
Treatments
Mice were kept under a 12-h light cycle and provided food and water ad libitum. For the lower L-T3 dose used in the TSH suppression, test mice were fed a low-iodine diet containing 0.15% propylthiouracil (LoI/PTU) (Harlan Teklad Co., Madison, WI) for 14 d, and 0.8 µg L-T3/100 g body weight (BW)·d was injected ip in the last 4 d. LoI/PTU was used to suppress the endogenous T3 production during the administration of the physiological (low dose) of L-T3. The high T3 dose of 5 µg L-T3/100 g BW·d used in the TSH suppression test and in the time course of T3 concentrations was administered for 4 d to animals receiving regular diet. Five WT and five Mct8–/y male littermates were used for each group of treatment. Mice were anesthetized 16 h after the last L-T3 injection and, after obtaining a blood sample, were perfused to remove blood from organs and tissues were collected. For the time course experiment with high L-T3 dose, blood was drawn at 3, 6, 16, and 20 h after the last injection.
Serum measurements
Serum total T4 and T3 concentration were measured by coated tube RIAs (Diagnostic Products, Los Angeles, CA) adapted for mouse serum using 25 and 50 µl serum, respectively. Total rT3 was measured in 50 µl serum by RIA using reagents from Adaltis Italia (Rino, Italy). TSH was measured in 50 µl serum using a sensitive, heterologous, disequilibrium, double-antibody precipitation RIA (14). Cholesterol and alkaline phosphatase were measured each on 10 µl serum using a clinical chemistry autoanalyzer.
Tissue T3 content
Before tissue collection, mice were perfused with heparinated PBS through a needle placed in the left ventricle. Tissues were rapidly collected on dry ice and stored at –80 C. T3 was extracted from brain and liver using a method previously described (15, 16), and T3 content was measured by RIA. Recovery was monitored in every batch of extraction by addition of the corresponding labeled iodothyronines to the tissues before homogenization.
Gene expression
Total RNA was extracted using phenol/guanidine isothiocyanate (TRIZOL, Invitrogen, Carlsbad, CA), and 2 µg total RNA was reverse transcribed using Superscript III RNase H Reverse Transcriptase Kit (Invitrogen) in the presence of 100 ng random hexamers. Reactions for the quantitation of mRNAs were performed in an ABI Prism 7000 Sequence Detection System (Applied Biosystems, Foster City, CA), using SYBR Green I as detector dye. The oligonucleotide primers were designed to cross introns. Primers used for Gsta2, Dio1, Dio2, and Dio3 are available upon request. Amplification of housekeeping gene RNA polymerase II was used as internal control (17).
D2 and D1 enzymatic activities
D2 enzymatic activity was performed as described (18) with the following modifications: 100 µg tissue homogenates in 100 µl reaction mixture containing 0.1 M phosphate buffer (pH 7), 1 mM EDTA, 20 mM dithiothreitol, 1 mM PTU, 100,000 cpm [125I]-T4, and 2 nM unlabeled T4 were incubated at 37 C for 1 h. Saturating levels of unlabeled T3 (1 µM) were added to the reaction mixture to inhibit the D3 enzyme. D1 enzymatic activity in liver was measured using [125I]-T4 as previously described (19) modified as follows: 20 µg tissue homogenates in 100 µl reaction mixture containing 0.1 M phosphate buffer (pH 7), 1 mM EDTA, 10 mM dithiothreitol, 100,000 cpm [125I]-T4, and 1 µM unlabeled T4 were incubated at 37 C for 30 min. The enzymatic activities expressed in femtomoles (for D2) and picomoles (for D1) per hour and milligrams of protein were corrected for nonenzymatic deiodination observed in the tissue-free controls.
Statistic analysis was performed using ANOVA. Data are represented as mean ± SD. P > 0.05 was considered not to be significant.
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Results |
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). The orientation of the genes contained in the cassette was reverse to the gene to be targeted to minimize the effect of the strong promoters on the locus. NeoR colonies were screened by Southern blot with probes outside of the homology arms (Fig. 1B). Male E14Tg1A.4 129P2 ES cells were used for targeting. Of a total of 307 NeoR clones, three were identified that were correctly targeted by homologous recombination, a targeting efficiency of 1/102 NeoR.
Generation of Mct8–/y mice
The three independently targeted clones in a 129P2/OlaHsd-derived ES cell line were injected into C57Bl/6J blastocysts. Fifteen high-percentage male chimeras were generated, and germline transmission was tested by mating with C57Bl/6J WT females. Expression of the Cre recombinase contained in the targeted Mct8 locus is activated in the testis of transmitting male chimeras (Fig. 1C) and recombines the three LoxP sites resulting in several possible alleles, including the null allele Mct8–. Here, we present the data regarding the null allele. Because the Mct8 locus is X-linked, there is no male to male inheritance; therefore, the transmission of the targeted allele was tested by genotyping only the female agouti pups born in the first generation (F1). F2 progeny were produced (Fig. 1D) by backcrossing the F1 heterozygous null females to WT C57Bl/6J males. Transmission of the null allele occurred in correct Mendelian ratios for an X-linked locus: of 120 pups from 14 litters, 26 (21.7%) were male null Mct8–/y, 33 (27.5%) were heterozygous females Mct8–/+, and 61 (50.8%) were WT (37 males, 24 females).
Thyroid phenotype of Mct8–/y mice
Mct8–/y mice are viable, fertile, and grow normally (7.4 ± 0.9 vs. 8 ± 1 g in WT at weaning and 21.2 ± 2.4 vs. 23.7 ± 2.5 g in WT at 6 wk of age). No obvious motor abnormalities were observed; mice ambulate and eat normally. Male Mct8–/y mice replicate the characteristic human thyroid phenotype, with significantly higher serum T3 and lower T4 and rT3 than their male WT littermates (Table 1). Carrier Mct8–/+ females have some of the TFT abnormalities, higher T3 levels compared with WT female littermates (117.6 ± 17.9 vs. 91.8 ± 8.1 ng/dl in WT, P < 0.02), lower rT3 (27.9 ± 10.3 vs. 41.7 ± 5.1 ng/dl in WT, P < 0.03) but similar T4 (4.3 ± 0.9 vs. 4.8 ± 0.3 µg/dl in WT, not significant).
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). Thus, the observed changes are due to the induced mutation rather than an ES clone-specific abnormality. Inbred mutant male mice (129) were generated (Table 1), and their TFT pattern was similar to that in mice of mixed genetic background. This indicates that the consequences of Mct8 deficiency on thyroid physiology are stronger than putative modifiers of thyroid function due to different genetic backgrounds.
Homozygous null female (Mct8–/–) mice were born from F2 intercrosses of male Mct8–/y and female Mct8–/+ mice. No WT females are born from this type of cross; thus, the comparison was done between Mct8–/+ and Mct8–/– female littermates. Their thyroid phenotype (Table 1) had the same characteristics as the phenotype of males Mct8–/y, indicating no gender-specific differences in the thyroid phenotype providing a proof of principle for the consequences of complete Mct8 loss. A corresponding human female has not been reported because the known males with MCT8 defect have not reproduced. For further investigations, we used the male Mct8–/y mice with their WT littermates for consistency of comparisons.
A T3 suppression test was used to investigate pituitary sensitivity to T3. This identical test has been used previously to test the sensitivity to T3 in mice deficient in the TH receptors ß and 
(22, 23). Serum TSH levels in 6-wk-old F2 male Mct8–/y untreated mice were not different compared with their WT littermates (Table 1). By 16 wk, differences in baseline serum TSH concentrations (at the limit of detection, <20 mU/liter in WT and 51.5 ± 16.2 mU/liter in Mct8–/y) became significant at P < 0.02. When fed a LoI/PTU diet, TSH increased similarly in both genotypes (6907 ± 3062 mU/liter in WT vs. 4937 ± 1754 mU/liter in Mct8–/y mice) and serum T3 levels decreased to the same level (58 ± 14 and 53 ± 10 ng/dl in WT and Mct8–/y mice, respectively). These values are not significantly different, and they are not graphed in Fig. 2. Administration of 0.8 µg/100 g BW·d L-T3, just sufficient to correct hypothyroidism induced by the LoI/PTU diet, failed to suppress the serum TSH in the Mct8–/y mice to the levels observed in the WT controls despite similar T3 serum levels (Fig. 2). A 6-fold higher L-T3 dose (5 µg/100 g BW·d) was able to achieve full TSH suppression in both genotypes (Fig. 2). These results show a relative pituitary resistance to T3 in the Mct8–/y mice and in addition demonstrate that T4 is responsible for maintaining the high serum T3 levels in Mct8 deficiency because both T3 treatment protocols result in undetectable (<0.25 µg/dl) serum T4 levels and similar serum T3 levels.
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) in 16-wk-old Mct8–/y and WT littermates, at baseline and after L-T3 treatment (5 µg/100 g BW·d), for 4 d to suppress the endogenous production, thus allowing the comparison of the distribution of equivalent amounts of T3 in mice that under basal condition have different concentrations. Serum was collected at 3, 6, 16, and 20 h after the last (fourth) L-T3 injection. Tissues were frozen after intracardiac perfusion with heparinated PBS. We chose to study the liver and brain because in the liver, several classes of TH transporters are known to be expressed, some of which are liver specific (24); therefore, functional redundancy is possible, whereas in brain, only two TH transporters are known to be expressed, Mct8 and Oatp1c1 (24). Their expression pattern does not overlap; therefore, no high degree of redundancy is expected.
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). In the liver of WT and Mct8–/y mice, changes in T3 concentrations paralleled those observed in serum over the same period of time (P = 0.9) (Fig. 3B). In the cerebrum of WT mice, T3 content was highest at 6 h, whereas T3 content in the Mct8–/y mice were 2 to 10 times lower at all times (P < 0.001) (Fig. 3C). These results indicate that the liver is not dependent on Mct8, despite its relatively high expression (1, 2, 3, 4, 5), and that other liver TH transporters ensure hepatic T3 transport resulting in levels that parallel serum. In contrast, lack of Mct8 results in brain-specific deficiency in TH.
Tissue-specific TH excess and deprivation in Mct8–/y mice
We further investigated the TH status in liver and brain of Mct8-deficient mice. In liver, the baseline T3 content was 2.3 times higher in Mct8–/y than in their WT littermates (Fig. 4A), thus reflecting the higher T3 serum levels in these mice. Serum cholesterol and alkaline phosphatase, markers of TH action on liver (25), showed changes compatible with a thyrotoxic state in the liver of Mct8–/y mice compared with their WT littermates (Fig. 4B). The significantly higher T3 content in the liver of Mct8–/y mice affected also the expression of TH target genes, glutathione S transferase 2 (Gsta2) (Fig. 4C) and D1 (Dio1) (Fig. 4D), normally down-regulated and up-regulated, respectively, by TH (23, 26). At baseline, the expression of Dio1 mRNA was 6.1 times higher (Fig. 4D), with D1 enzymatic activity being 3.1 times higher (Fig. 4E) in the liver of Mct8–/y than in WT mice. After L-T3 treatment, Dio1 mRNA levels were comparable in both genotypes in agreement with the equalization of T3 content (Fig. 3B). Similarly, basal Gsta2 mRNA levels were significantly lower in Mct8–/y mice and become equally reduced in Mct8–/y and WT mice after treatment with the TSH-suppressive dose of L-T3. These results demonstrate a relatively thyrotoxic state at baseline in the liver of Mct8–/y mice, reflecting the higher serum concentration of T3, indicating that in these mice, the transfer of T3 from blood to liver is mediated through TH transmembrane carriers other than Mct8 (24).
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). This tissue is heterogeneous in cell types and genes regulated by TH, and their developmentally regulated expression is restricted to discrete population of cells (27, 28). Therefore, it is not appropriate to measure in whole-organ mRNAs of TH-regulated genes with limited cell expression. We measured instead Dio2 expression and activity to assess the overall thyroid status. The lower T3 content was accompanied by a 1.6-fold higher mRNA expression of Dio2 in the Mct8–/y mice (Fig. 5B), whereas the D2 enzymatic activity was increased by 10.6-fold (Fig. 5D), likely due to posttranscriptional regulation of the D2 protein (29, 30). We also measured Dio3 mRNA at baseline and after T3 treatment. Although Dio3 has been shown to respond to T3 (29, 30), the mechanism for its positive regulation is not known. Baseline Dio3 expression was not significantly different between the two genotypes (Fig. 5C), and T3 treatment increased Dio3 mRNA in WT mice but did not change the expression in Mct8–/y mice, in agreement with the impaired T3 uptake demonstrated in the cerebrum (Fig. 3C). These results demonstrate the Mct8 dependency of the brain for adequate T3 levels and uncover the increase in D2 activity, likely a consequence of the low T4 levels and a compensatory mechanism to protect a minimum necessary local supply of T3 as it has been demonstrated in rat hypothyroid brain (31).
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Discussion |
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The thyroid phenotype of Mct8 null (Mct8–/y) mice replicates the phenotype observed in humans. The characteristic unusual TFT have been found in male Mct8–/y mice originating from all three independently targeted ES cell clones on both C57Bl/6J:129Sv mixed and 129Sv genetic background. Furthermore, female Mct8–/– born from F2 intercrosses have the same pattern of TFT as the males. The consistency of the thyroid phenotype in different genetic backgrounds indicates that the consequences of Mct8 defect on thyroid physiology are stronger than putative modifiers of thyroid function in different strains.
The fact that the neurological manifestations present in male humans with MCT8 defects are not replicated in the mouse model might be due to species-specific regulation of intracellular TH availability and TH demands for normal function of central nervous system. The absence of a neurologic phenotype in mice that are hypothyroid at the brain level is not totally unexpected because other instances of neurologic symptoms associated with hypothyroidism, such as the spastic neurologic cretinism associated with iodine deficiency in humans, are not replicated in mouse models of iodine deficiency (33). It is possible that subtle abnormalities are present in the brains of Mct8-deficient mice, and detailed studies focused on investigation of the consequences of Mct8 defect on central nervous system are needed to elucidate this aspect.
At 6 wk, TSH levels were similar in male WT and Mct8–/y mice, but by 16 wk, the TSH levels in Mct8–/y mice slightly increased. Pituitary sensitivity was tested using a standardized test of TSH suppression for mice (22, 23). L-T3 levels sufficient to correct TH deficiency in WT mice were unable to equally suppress the TSH in Mct8–/y mice, therefore establishing the reduced ability of the circulating T3 to reach the thyrotrophs and/or hypothalamus. Six-fold higher doses of L-T3 were able to suppress serum TSH levels in the Mct8–/y mice, indicating a relative central resistance likely due to impaired uptake of L-T3. The fact that similar serum T3 levels are achieved in both genotypes when the endogenous T4 production is suppressed indicates that T4 is responsible for maintaining the high serum T3 levels characteristic for Mct8 deficiency.
To assess T3 uptake and its tissue availability, we examined the time course of T3 disappearance from serum and tissues after administration for 4 d of a daily supraphysiological dose of L-T3. The goal of this protocol was to suppress the endogenous production of TH, thus allowing the comparison of the responses to the equivalent amount of T3 in mice that under basal conditions have different concentrations of TH. Serum T3 levels and liver T3 content followed a similar pattern after the last L-T3 injection in mice from both genotypes, indicating that degradation of T3 is not reduced in this defect. T3 uptake in the cerebrum of WT mice occurred later than in the liver, whereas the uptake in the cerebrum of in Mct8–/y mice was minimal, up to 10 times lower. These results demonstrate tissue-specific differences in TH uptake in Mct8-deficient mice dependent upon the redundancy in TH transport.
To study the consequences of Mct8-dependent TH uptake differences, we measured tissue T3 content in the liver of 16-wk-old mice, perfused to remove blood-derived T3, and measured the expression of genes positively and negatively regulated by TH, at baseline and after L-T3 treatment. Liver T3 content was significantly higher in the Mct8–/y mice at baseline, reflecting the circulating T3 levels. The consequences of this T3 level were confirmed by its effect on TH-responsive genes, Dio1 (29) and Gsta2 (26). The significant differences found between Mct8–/y and WT mice at baseline were abrogated by treatment with high-dose L-T3 that equilibrated the serum T3 levels. In addition, the baseline hepatic thyrotoxicosis resulted in decreased serum cholesterol and increased alkaline phosphatase in Mct8–/y mice compared with WT, similar to the lower serum cholesterol levels and increased SHBG reported in humans with MCT8 mutations (34) and mice given TH (25).
The TH deficiency in brain, as demonstrated by low baseline tissue T3 content, is undoubtedly the consequence of reduced T3 uptake in this tissue, which contributes to further augment the serum T3 concentration. This hypothyroid state in cerebrum, also maintained by the low serum T4, results in a 10.6-fold increase in D2 enzymatic activity by posttranscriptional mechanisms, such as increased half-life of the enzyme and decreased degradation (29, 30).
Our findings of coexistent TH excess and deficiency in Mct8 knockout mice can explain in part the mechanisms responsible for the TFT pattern observed in Mct8 deficiency. Several tissue-specific events come into play. Multiple TH transporters expressed in liver allow entry of serum T3 producing hepatic thyrotoxicosis. Furthermore, the increased T3 content in liver of Mct8–/y mice stimulates Dio1 expression and D1 enzymatic activity. The latter increases the conversion of T4 to T3, which likely results in the consumption of T4 and further increase in T3. The increased D1 enzymatic activity in liver also stimulates the metabolism of rT3. This, together with the decreased rT3 production expected from 5-deiodination of T4, play a role in the low serum rT3 levels characteristic in Mct8 deficiency. The coexistence of increased D1 and D2 activity stimulated by opposite states of intracellular TH availability has an additive consumptive effect on T4 levels. In cerebrum, the D2 activity functions to maintain minimal local levels of T3 in the context of Mct8 deficiency, whereas the thyrotoxic environment in the liver results in increased D1 activity and due to the size effect of this organ contributes to the high serum T3 levels.
The in vivo and in vitro studies carried out in these Mct8-deficient mice have provided insight into the pathophysiology of this defect. Deiodinases modulate the intracellular availability of active T3 in a tissue-specific fashion. Due to the complex nature of deiodinase regulation and differences in tissue-specific TH availability, the overall increased 5' deiodination is not counterbalanced by 5 deiodination. This is maintained through a cycle probably triggered by the impaired uptake of TH in Mct8-dependent tissues and the subsequent increased T3 levels. This knockout mouse model represents a useful tool to study the pathophysiology of TFT abnormalities characteristic in MCT8 deficiency and demonstrates the complexity of this defect, with tissue-specific TH excess and deficiency depending on the redundancy in supply of TH through various classes of TH transporters.
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Acknowledgments |
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Footnotes |
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First Published Online May 18, 2006
Abbreviations: BW, Body weight; D1, deiodinase 1; D2, deiodinase 2; DTA, diphtheria toxin A; ES, embryonic stem; gDNA, genomic DNA; LoI/PTU, low-iodine diet containing 0.15% propylthiouracil; MCT, monocarboxylate transporter; NeoR, neomycin resistance; TFT, thyroid function test; TH, thyroid hormone; WT, wild type.
Received March 27, 2006.
Accepted for publication May 8, 2006.
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J. Jansen, E. C. H. Friesema, M. H. A. Kester, C. Milici, M. Reeser, A. Gruters, T. G. Barrett, E. E. Mancilla, J. Svensson, J.-L. Wemeau, et al. Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2378 - 2381. [Abstract] [Full Text] [PDF]
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S. Suzuki, N. Suzuki, J.-i. Mori, A. Oshima, S. Usami, and K. Hashizume {micro}-Crystallin as an Intracellular 3,5,3'-Triiodothyronine Holder in Vivo Mol. Endocrinol., April 1, 2007; 21(4): 885 - 894. [Abstract] [Full Text] [PDF]
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J. Bernal Role of Monocarboxylate Anion Transporter 8 (MCT8) in Thyroid Hormone Transport: Answers from Mice. Endocrinology, September 1, 2006; 147(9): 4034 - 4035. [Full Text] [PDF]
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