Tissue-Specific Function of Thyroid Hormone Transporters: New Insights from Mouse Models

Abstract

Thyroid hormone (TH) transporters are required for cellular transmembrane passage of TH and are thus mandatory for proper TH metabolism and action. Consequently, inactivating mutations in TH transporters such as MCT8 or OATP1C1 can cause tissue- specific changes in TH homeostasis. As the most prominent example, patients with MCT8 mutations exhibit elevated serum T3 levels, whereas their CNS appear to be in a TH deficient state. Here, we will briefly summarize recent studies of mice lacking Mct8 alone or in combination with the TH transporters Mct10 or Oatp1c1 that shed light on many aspects and pathogenic events underlying global MCT8 deficiency and also underscore the contribution of Mct10 and Oatp1c1 in tissue-specific TH transport processes. Moreover, development of conditional knock-out mice that allow a cell-specific inactivation of TH transporters in distinct tissues, disclosed cell-specific changes in TH signaling, thereby highlighting the pathophysiological significance of local control of TH action.

Monocarboxylate Transporter 8 Deficiency: Delayed or Permanent Hypomyelination?

“…Lack of TH uptake in global knockouts such as the Mct8/Oatp1c1 double KO mouse affects nearly all CNS cell types controlling sensorimotor functions, and therefore do not allow addressing how deficient myelination contributes to altered behavior. Use of single cell type genetic technologies such as conditional KO mice or zebrafish lacking MCT8 or both MCT8 and OATP1C1 (135) in OPCs/oligodendrocytes could enable isolating neuronal or neuro-muscular defects caused by pathologies linked to other cell types. Measuring electric potentials across major axonal tracts might also help to identify impaired neuromuscular communication.…”

Seven Years of Active Thyroid Hormone Research in Germany: Thyroid Hormone Action beyond Classical Concepts

“…Here, the groups of Schweizer [8] and Krause [9] unravelled molecular insights into the architecture and function of transmembrane transporters and their role in pathophysiology. Sophisticated mouse models have been developed that serve to understand principles of TH up-take into TH-dependent tissues as shown by Heuer and team [10], which were pivotal for many studies to understand tissue-specific TH action (see below).…”

Tentative Application of a Streamlined Protocol to Determine Organ-Specific Regulations of Deiodinase 1 and Dehalogenase Activities as Readouts of the Hypothalamus-Pituitary-Thyroid-Periphery-Axis

“…Local mechanisms of hormonal regulation were described, including TH trans-membrane or trans-barrier (e.g., blood-brain-barrier or brain-placenta-barrier) transport, local TH activation or inactivation by deiodination, elimination via sulfation or glucuronidation, and a complex interplay between different isoforms of TH-receptors (TR) ( Murk et al, 2013 ) as well as canonical and non-canonical TR signalling. For most of these local mechanisms, a substantial impact on proper TH action was impressively shown by respective pathologies due to (in-)activating mutations in patients ( Afink et al, 2008 ; Dumitrescu et al, 2010 ; van Geest et al, 2021 ) or genetically modified mice ( Fujisawa et al, 2020 ; Salveridou et al, 2020 ; Morte et al, 2021 ).…”