The tissue-specific role of the murine thyroid hormone transporters Mct8 and Mct10

• Applicant: Professorin Dr. Heike Heuer
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221028883

Thyroid hormone (TH) actions and metabolism are intracellular events that require the transport of TH across the plasma membrane. This process is facilitated by TH transporters of which the monocarboxylate transporter 8 (MCT8) has been most intensively analyzed. In humans, inactivating mutations in the X-linked MCT8 gene are associated with a severe form of psychomotor retardation in combination with abnormal serum TH parameters. We recently provided a detailed description of Mct8 deficient mice that despite the absence of overt neurological symptoms exhibit the same unusual serum TH parameters as patients carrying MCT8 mutations. As a consequence of the altered TH profile as well as changes in TH transport in various organs, Mct8 ko mice exhibit a complex phenotype of tissue-specific TH excess and deprivation that impedes the analysis of the tissue-specific role of Mct8. Here, we aim to unravel the consequences of a cell-specific inactivation of Mct8 on tissue homeostasis as well as on the serum TH profile by taking advantage of conditional Mct8 mouse mutants expressing cre-recombinase in a cell-specific manner. We will particularly study the consequence of a cell-specific inactivation of Mct8 in the liver, thyroid gland, and the kidney as all three tissues are greatly affected by Mct8 deficiency and have been suggested to be involved in the generation of the abnormal serum TH levels. In addition, we aim to dissect the cell-specific function of Mct8 in the hypothalamus where Mct8 is present in neurons, capillary cells and tanycytes. We further include in our studies mouse mutants that are also deficient in the thyroid hormone transporter Mct10 as our analysis using conventional Mct8/Mct10 deficient mouse mutants indicated a concerted action of both TH transporters in the kidney, liver and thyroid. Most importantly, inactivation of Mct10 leads to a partial normalization of the abnormal serum TH levels characteristic for Mct8 deficiency, and by using conditional mouse mutants we aim to unravel the underlying mechanism.In summary, we aim to elucidate the significance of Mct8 and Mct10 in facilitating TH access to its target tissue and to further elucidate mechanisms that cause the abnormal serum thyroid parameters in Mct8 deficient mice. We also hope our studies will provide an insight to ameliorate the devastating conditions of patients with MCT8 mutations

• DFG Programme: Priority Programmes
• Subproject of: SPP 1629: THYROID TRANS ACT - Translation of Thyroid Hormone Actions beyond Classical Concepts
• International Connection: Belgium
• Cooperation Partner: Professorin Dr. Veerle Darras