Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain
- University of Chicago Medical Center, United States
- Institute of Experimental Medicine, Hungary
- University of Chicago, United States
Abstract
The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for supplementary figures 2
Article and author information
Author details
Federico Salas-Lucia
Funding
The Hungarian National Brain Research Program 2 (NRDIO K125247)
- Csaba Fekete
National Institute of Diabetes and Digestive and Kidney Diseases (DK58538)
- Balázs Gereben
National Institute of Diabetes and Digestive and Kidney Diseases (DK58538,DK65055)
- Antonio Bianco
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee at the University of Chicago (#72577) or by the Animal Welfare Committee at the Institute of ExperimentalMedicine and followed the American Thyroid Association Guide to investigating TH economy and action in rodents and cell models (52).
Copyright
© 2023, Salas-Lucia et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain
eLife 12:e82683.
https://doi.org/10.7554/eLife.82683
