Abstract
Hypothalamic neurosecretory systems are fundamental regulatory circuits influenced by thyroid hormone. Monocarboxylate-transporter-8 (MCT8)-mediated uptake of thyroid hormone followed by type 3 deiodinase (D3)-catalyzed inactivation represent limiting regulatory factors of neuronal T3 availability. In the present study we addressed the localization and subcellular distribution of D3 and MCT8 in neurosecretory neurons and addressed D3 function in their axons. Intense D3-immunoreactivity was observed in axon varicosities in the external zone of the rat median eminence and the neurohaemal zone of the human infundibulum containing axon terminals of hypophysiotropic parvocellular neurons. Immuno-electronmicroscopy localized D3 to dense-core vesicles in hypophysiotropic axon varicosities. N-STORM-superresolution-microscopy detected the active center containing C-terminus of D3 at the outer surface of these organelles. Double-labeling immunofluorescent confocal microscopy revealed that D3 is present in the majority of GnRH, CRH and GHRH axons but only in a minority of TRH axons, while absent from somatostatin-containing neurons. Bimolecular-Fluorescence-Complementation identified D3 homodimers, a prerequisite for D3 activity, in processes of GT1-7 cells. Furthermore, T3-inducible D3 catalytic activity was detected in the rat median eminence. Triple-labeling immunofluorescence and immuno-electronmicroscopy revealed the presence of MCT8 on the surface of the vast majority of all types of hypophysiotropic terminals. The presence of MCT8 was also demonstrated on the axon terminals in the neurohaemal zone of the human infundibulum. The unexpected role of hypophysiotropic axons in fine-tuned regulation of T3 availability in these cells via MCT8-mediated transport and D3-catalyzed inactivation may represent a novel regulatory core mechanism for metabolism, growth, stress and reproduction in rodents and humans.
Highlights
Thyroid hormone is essential to normal brain development and function [1,2]
We demonstrate that in the median eminence, D3 is present in subsets of GnRH, GHRH- CRH and thyrotropin-releasing hormone (TRH) containing axon terminals in a system specific level, and is subjected to trafficking in axonal dense core vesicles
The highest density was observed in the external zone of the median eminence (Fig. 1A–B), where the axons of the hypophysiotropic neurons accumulated around the portal capillary system
Summary
Thyroid hormone is essential to normal brain development and function [1,2]. Thyroxine (T4) is transported through the bloodbrain barrier and converted to triiodothyronine (T3) to bind and activate thyroid hormone receptors (TR). This pathway is catalyzed by type 2 deiodinase (D2) in glial cells [3,4,5] from which T3 exits for uptake into TR-containing neurons to establish a transcriptional footprint [6]. The hypothalamic hypophysiotropic neurosecretory system regulates metabolism, stress, growth and reproduction [11,12] in a thyroid hormone-dependent manner. Thyroid hormone is necessary for ACTH and GH secretion from the anterior pituitary [15,16,17]
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