{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:34:02Z","timestamp":1788482042557,"version":"build-2803163510"},"reference-count":52,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2020,2,1]],"date-time":"2020-02-01T00:00:00Z","timestamp":1580515200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2020,2]]},"abstract":"\n Background:<\/jats:title>\n \n Patients with mutations of the thyroid hormone receptor alpha (\n THRA<\/jats:italic>\n ) gene show resistance to thyroid hormone alpha (RTH\u03b1). No amendable mouse models are currently available to elucidate deleterious effects of TR\u03b11 mutants during early development. Zebrafish with transient suppressed expression by morpholino knockdown and ectopic expression of TR\u03b11 mutants in the embryos have been reported. However, zebrafish with germline transmittable mutations have not been reported. The stable expression of\n thra<\/jats:italic>\n mutants from embryos to adulthood facilitated the study of molecular actions of TR\u03b11 mutants during development.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n In contrast to human and mice, the\n thra<\/jats:italic>\n gene is duplicated in zebrafish,\n thraa<\/jats:italic>\n , and\n thrab<\/jats:italic>\n . Using CRISPR\/Cas9-mediated targeted mutagenesis, we created dominant negative mutations in the two duplicated\n thra<\/jats:italic>\n genes. We comprehensively analyzed the molecular and phenotypic characteristics of mutant fish during development.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Adult and juvenile homozygous\n thrab 1-bp ins (m\/m)<\/jats:italic>\n mutants exhibited severe growth retardation, but adult homozygous\n thraa 8-bp ins (m\/m)<\/jats:italic>\n mutants had very mild growth impairment. Expression of the growth hormone (\n gh1<\/jats:italic>\n ) and insulin-like growth factor 1 was markedly suppressed in homozygous\n thrab 1-bp ins (m\/m)<\/jats:italic>\n mutants. Decreased messenger RNA and protein levels of triiodothyronine-regulated keratin genes and inhibited keratinocyte proliferation resulted in hypoplasia of the epidermis in adult and juvenile homozygous\n thrab 1-bp ins (m\/m)<\/jats:italic>\n mutants, but not homozygous\n thraa 8-bp ins (m\/m)<\/jats:italic>\n mutants. RNA-seq analysis showed that homozygous\n thrab 1-bp ins (m\/m)<\/jats:italic>\n mutation had global impact on the functions of the adult pituitary. However, no morphological defects nor any changes in the expression of\n gh1<\/jats:italic>\n and keratin genes were observed in the embryos and early larvae. Thus, mutations of either the\n thraa<\/jats:italic>\n or\n thrab<\/jats:italic>\n gene did not affect initiation of embryogenesis. But the mutation of the\n thrab<\/jats:italic>\n gene, but not the\n thraa<\/jats:italic>\n gene, is detrimental in postlarval growth and skin development.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n The\n thra<\/jats:italic>\n duplicated genes are essential to control temporal coordination in postlarval growth and development in a tissue-specific manner. We uncovered novel functions of the duplicated\n thra<\/jats:italic>\n genes in zebrafish in development. These mutant zebrafish could be used as a model for further analysis of TR\u03b11 mutant actions and for rapid screening of therapeutics for RTH\u03b1.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1089\/thy.2019.0598","type":"journal-article","created":{"date-parts":[[2020,1,18]],"date-time":"2020-01-18T01:14:57Z","timestamp":1579310097000},"page":"314-328","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":17,"title":["Generation of Novel Genetic Models to Dissect Resistance to Thyroid Hormone Receptor \u03b1 in Zebrafish"],"prefix":"10.1177","volume":"30","author":[{"given":"Cho Rong","family":"Han","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Holmsen","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Carrington","sequence":"additional","affiliation":[{"name":"Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Bishop","sequence":"additional","affiliation":[{"name":"Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelin Jack","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Starost","sequence":"additional","affiliation":[{"name":"Division of Veterinary Resources, Diagnostic and Research Services Branch, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Meltzer","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raman","family":"Sood","sequence":"additional","affiliation":[{"name":"Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Liu","sequence":"additional","affiliation":[{"name":"Zebrafish Core, Translational and Functional Genomics 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