A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion.

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Thyroid hormones (T4 and T3) are crucial for vertebrate life, with deficiency causing hypothyroidism in 5-10% of the global population.
• Thyroglobulin (Tg) is the precursor for thyroid hormone synthesis, containing regions for T4 and T3 production.
• The CholinEsterase-Like (ChEL) domain of Tg is primarily responsible for T3 synthesis.

Purpose of the Study:

• To investigate the functional consequences of engineering thyroidal T3 synthesis independent of T4.
• To explore the regulation of T3 production and its tissue-specific actions.
• To understand the implications for thyroid hormone replacement therapy.

Main Methods:

• CRISPR/Cas9-mediated mutagenesis was used to knock in secretory ChEL into the endogenous Tg locus.
• Analysis of homozygous knock-in mice for thyroidal hormone synthesis, TSH levels, and goiter formation.
• Assessment of hepatic markers for thyroid hormone action, locomotor activity, and anxiety-like behavior.

Main Results:

• Homozygous knock-in mice synthesized T3 thyroidally but were largely deficient in T4 synthesis.
• T3 production in knock-in mice was regulated by thyrotropin (TSH), unlike conventional hypothyroidism.
• Despite normal circulating T3, knock-in mice showed elevated TSH, goiter, impaired activity, and increased anxiety, indicating T4 deficiency effects.

Conclusions:

• Engineered thyroidal T3 synthesis highlights the distinct roles of T4 and T3 in vivo.
• TSH regulates T3 production when T4 synthesis is impaired.
• Findings underscore the importance of considering tissue-specific T3 and T4 actions in thyroid hormone replacement therapy.