{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T05:48:27Z","timestamp":1773294507401,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["K01-DK125448"],"award-info":[{"award-number":["K01-DK125448"]}]},{"name":"National Institutes of Health","award":["R01-DK132017"],"award-info":[{"award-number":["R01-DK132017"]}]},{"name":"National Institutes of Health","award":["R01-DK15070"],"award-info":[{"award-number":["R01-DK15070"]}]},{"name":"Chapman University startup funds","award":["K01-DK125448"],"award-info":[{"award-number":["K01-DK125448"]}]},{"name":"Chapman University startup funds","award":["R01-DK132017"],"award-info":[{"award-number":["R01-DK132017"]}]},{"name":"Chapman University startup funds","award":["R01-DK15070"],"award-info":[{"award-number":["R01-DK15070"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u201310% of the world\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms26157166","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T15:19:22Z","timestamp":1753370362000},"page":"7166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Genetically-Engineered Thyroid Gland Built for Selective Triiodothyronine Secretion"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3547-5458","authenticated-orcid":false,"given":"Cintia E.","family":"Citterio","sequence":"first","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berenice","family":"Morales-Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8410-5584","authenticated-orcid":false,"given":"Catherine","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessie","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibrahim","family":"Metawea","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David P.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Department of Medicine and Pediatrics and Committees on Genetics, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mantzouratou, P., Lavecchia, A.M., and Xinaris, C. 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