{"doi":"10.3390/ijms26157166","title":"A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion","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.","journal":"International Journal of Molecular Sciences","year":2025,"id":545544,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1436815,"name":"Berenice Morales-Rodriguez","orcid":null,"position":1,"is_corresponding":false},{"id":277161,"name":"Xiao-Hui Liao","orcid":"0000-0002-9860-2709","position":2,"is_corresponding":false},{"id":1436816,"name":"Catherine N. Vu","orcid":null,"position":3,"is_corresponding":false},{"id":738608,"name":"Rachel Nguyen","orcid":"0000-0001-7374-9985","position":4,"is_corresponding":false},{"id":1436817,"name":"Jessie Tsai","orcid":null,"position":5,"is_corresponding":false},{"id":348337,"name":"Jennifer Lê","orcid":"0000-0002-6692-0884","position":6,"is_corresponding":false},{"id":1436818,"name":"Ibrahim Metawea","orcid":null,"position":7,"is_corresponding":false},{"id":289733,"name":"Ming Liu","orcid":"0000-0003-2665-4072","position":8,"is_corresponding":false},{"id":258938,"name":"David P. Olson","orcid":"0000-0001-9249-7760","position":9,"is_corresponding":false},{"id":277162,"name":"Samuel Refetoff","orcid":"0000-0003-0164-8231","position":10,"is_corresponding":false},{"id":33730,"name":"Peter Arvan","orcid":"0000-0002-4007-8799","position":11,"is_corresponding":false},{"id":262545,"name":"Cintia E. Citterio","orcid":"0000-0002-3547-5458","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:53:23.001995Z","pmid":"40806299","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}