A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion

Authors

Cintia E. Citterio, Chapman UniversityFollow
Berenice Morales-Rodriguez, Chapman UniversityFollow
Xiao-Hui Liao, The University of Chicago
Catherine Vu, Chapman University
Rachel Nguyen, Chapman University
Jessie Tsai, Chapman University
Jennifer Le, Chapman University
Ibrahim Metawea, University of Michigan - Ann Arbor
Ming Liu, Tianjin Medical University General Hospital
David P. Olson, University of Michigan - Ann Arbor
Samuel Refetoff, The University of Chicago
Peter Arvan, University of Michigan - Ann Arbor

Document Type

Article

Publication Date

7-24-2025

Abstract

Thyroid hormones (thyroxine, T₄, and triiodothyronine, T₃) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5–10% of the world’s population. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), a large iodoglycoprotein consisting of upstream regions I-II-III (responsible for synthesis of most T₄) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T₃, which can also be generated extrathyroidally by T₄ deiodination). Using CRISPR/Cas9-mediated mutagenesis, we engineered a knock-in of secretory ChEL into the endogenous TG locus. Secretory ChEL acquires Golgi-type glycans and is properly delivered to the thyroid follicle lumen, where T₃ is first formed. Homozygous knock-in mice are capable of thyroidal T₃ synthesis but largely incompetent for T₄ synthesis such that T₄-to-T₃ conversion contributes little. Instead, T₃ production is regulated thyroidally by thyrotropin (TSH). Compared to cog/cog mice with conventional hypothyroidism (low serum T₄ and T₃), the body size of ChEL-knock-in mice is larger; although, these animals with profound T₄ deficiency did exhibit a marked elevation of serum TSH and a large goiter, despite normal circulating T₃ levels. ChEL knock-in mice exhibited a normal expression of hepatic markers of thyroid hormone action but impaired locomotor activities and increased anxiety-like behavior, highlighting tissue-specific differences in T₃ versus T₄ action, reflecting key considerations in patients receiving thyroid hormone replacement therapy.

Comments

This article was originally published in International Journal of Molecular Sciences , volume 26, issue 15, in 2025. https://doi.org/10.3390/ijms26157166

Recommended Citation

Citterio, C.E.; Morales-Rodriguez, B.; Liao, X.-H.; Vu, C.; Nguyen, R.; Tsai, J.; Le, J.; Metawea, I.; Liu, M.; Olson, D.P.; et al. A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion. Int. J. Mol. Sci. 2025, 26, 7166. https://doi.org/10.3390/ijms26157166

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.