Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Center for Biomedical Research on Rare Diseases (Ciberer U708), Madrid, Spain.
Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany.
Thyroid. 2021 Jun;31(6):985-993. doi: 10.1089/thy.2020.0649. Epub 2021 Mar 18.
The monocarboxylate transporter 8 (Mct8) protein is a primary thyroxine (T4) and triiodothyronine (T3) (thyroid hormone [TH]) transporter. Mutations of the MCT8-encoding, gene alter thyroid function and TH metabolism and severely impair neurodevelopment (Allan-Herndon-Dudley syndrome [AHDS]). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is believed that Mct8 deficiency in mice is compensated by T4 transport through the -encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the -encoded type 2 deiodinase, thus preventing brain hypothyroidism. The / (MO) and / (MD) double knockout (KO) mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, respectively, should be appropriate models of AHDS. Our goal was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KO mice. We performed RNA sequencing by using RNA from the cerebral cortex and striatum of SH mice and the double KO mice on postnatal days 21-23. Real-time polymerase chain reaction was used to confirm RNA-Seq results in replicate biological samples. Cell type involvement was assessed from cell type-enriched genes. Functional genomic differences were analyzed by functional node activity based on a probabilistic graphical model. Each of the three conditions gave a different pattern of gene expression, with partial overlaps. SH gave a wider and highest variation of gene expression than MD or MO. This was partially due to secondary gene responses to hypothyroidism. The set of primary transcriptional T3 targets showed a tighter overlap, but quantitative gene responses indicated that the gene responses in SH were more severe than in MD or MO. Examination of cell type-enriched genes indicated cellular differences between the three conditions. The results indicate that the neurological impairment of AHDS is too severe to be fully explained by TH deprivation only.
单羧酸转运蛋白 8（Mct8）蛋白是甲状腺素（T4）和三碘甲状腺原氨酸（T3）（甲状腺激素[TH]）的主要转运蛋白。Mct8 编码基因的突变改变了甲状腺功能和 TH 代谢，严重损害了神经发育（Allan-Herndon-Dudley 综合征[AHDS]）。Mct8 缺陷小鼠表现出甲状腺改变，但缺乏神经学迹象。据信，Mct8 缺陷在小鼠中通过编码的有机阴离子转运多肽 1c1（Oatp1c1）转运 T4 得到补偿。这使得局部脑生成足够的 T3 由编码的 2 型脱碘酶，从而防止脑甲状腺功能减退。缺乏 T4 和 T3 转运或 T3 转运和 T4 脱碘的 /（MO）和 /（MD）双敲除（KO）小鼠分别应是 AHDS 的合适模型。我们的目标是比较甲状腺阻断引起的全身性甲状腺功能减退（SH）引起的脑甲状腺功能减退与双 KO 小鼠中存在的脑甲状腺功能减退。我们对 SH 小鼠和双 KO 小鼠出生后第 21-23 天的大脑皮层和纹状体进行了 RNA 测序。实时聚合酶链反应用于在重复的生物学样本中确认 RNA-Seq 结果。通过细胞类型丰富基因评估细胞类型参与。通过基于概率图形模型的功能节点活性分析功能基因组差异。三种情况中的每一种都给出了不同的基因表达模式，存在部分重叠。SH 比 MD 或 MO 产生了更广泛和更高的基因表达变化。这部分是由于甲状腺功能减退的次级基因反应。原发性转录 T3 靶基因集显示出更紧密的重叠，但定量基因反应表明，SH 中的基因反应比 MD 或 MO 更严重。对细胞类型丰富基因的检查表明三种情况之间存在细胞差异。结果表明，AHDS 的神经损伤过于严重，仅通过 TH 剥夺无法完全解释。
