Thyroid hormone transporters and deiodinases in the developing human hypothalamus

Abstract

Objective: Thyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus. Design: Fifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied. Methods: Sections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3. Results: We found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age. Conclusions: This study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells.

Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study

“…The relative importance of the thyroid hormone transporter in species may differ substantially [47] and so may their relative expression in various tissues and at different points of time during human life [48]. It has been claimed that the OATP1C1 gene is relatively less expressed in humans compared to other species and restricted to very specific areas of the human brain.…”

Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

“…In vertebrates, MCT8 is expressed in neurons, glial cells, and endothelial cells of the vascular system, including in the BBB (Friesema et al, 2012; Müller and Heuer, 2014; Pizzagalli et al, 2002; Roberts et al, 2008; Vatine et al, 2013). In contrast to humans, the TH transporter OATP1C1 is profoundly expressed in the BBB of mice.…”

“…AHDS is associated with mutations in monocarboxylate transporter 8 ( MCT8 , SLC 1 6A2 ), which transports TH across the cell membrane (Ceballos et al, 2009; Friesema et al, 2003). MCT8 is primarily expressed in the CNS, vascular system and blood–brain barrier (BBB) (Friesema et al, 2012; Pizzagalli et al, 2002; Roberts et al, 2008). In order to study the mechanism underlying AHDS, an Mct8 knockout ( Mct8 -KO) mouse model was established.…”

Scope and limitations of iodothyronine deiodinases in hypothyroidism

“…For example, in the human fetal hypothalamus, a developmental dependency and coordinated expression of DIO2 and DIO3 occurs in combination with the various thyroid-hormone transporters. 77 …”