{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:43:29Z","timestamp":1787849009188,"version":"build-2784847793"},"reference-count":55,"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":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      GLIS3 (GLI-Similar protein 3) is a transcription factor involved in several cellular processes. Homozygous mutations in the\n                      <jats:italic toggle=\"yes\">GLIS3<\/jats:italic>\n                      gene have been typically associated with neonatal diabetes and congenital hypothyroidism (CH) in a syndrome called NDH. NDH patients present developmental abnormalities including endocrine pancreas defects and a spectrum of thyroid abnormalities, mainly including thyroid dysgenesis (TD). The mouse models revealed a key role of\n                      <jats:italic toggle=\"yes\">Glis3<\/jats:italic>\n                      in pancreatic islets but not in early thyroid development, as\n                      <jats:italic toggle=\"yes\">Glis3<\/jats:italic>\n                      was described to retain a role in regulating thyroid hormone synthesis downstream the thyrotropin (TSH)\/TSHR signaling pathway and in postnatal follicle proliferation. Hence, in this study, we have been taking advantage of the zebrafish model to gain insights on the Glis3 activity during thyroid organogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Transient\n                      <jats:italic toggle=\"yes\">glis3-<\/jats:italic>\n                      knockdown zebrafish embryos (called\n                      <jats:italic toggle=\"yes\">glis3<\/jats:italic>\n                      morphants) were generated by the microinjection of specific\n                      <jats:italic toggle=\"yes\">glis3<\/jats:italic>\n                      morpholinos at one- to two-cell stage to analyze the thyroid phenotype\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . Several additional analyses (\n                      <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                      hybridization, immunohistochemistry, and pharmacological treatments) were performed for further molecular characterization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The analysis of thyroid embryonic development revealed that Glis3 is involved in early steps of thyroid specification.\n                      <jats:italic toggle=\"yes\">glis3<\/jats:italic>\n                      morphants exhibited a reduced expression of the early transcription factors\n                      <jats:italic toggle=\"yes\">nkx2.4<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">pax2a<\/jats:italic>\n                      at the thyroid primordium level, which is not caused by changes in proliferation or apoptosis of the pharyngeal endoderm. As a result, the differentiated thyroid tissue in morphants appeared reduced in size with decreased expression of\n                      <jats:italic toggle=\"yes\">tg<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">slc5a5<\/jats:italic>\n                      , a low number of thyroxine (T4)-producing follicles, associated with an elevation of\n                      <jats:italic toggle=\"yes\">tshba<\/jats:italic>\n                      (homologous of the human TSH\u03b2), thus resembling the clinical and biochemical manifestations of patients with TD. Interestingly,\n                      <jats:italic toggle=\"yes\">glis3<\/jats:italic>\n                      morphants have pancreatic \u03b2-cell defects, but not liver defects.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      data also demonstrated that Glis3 is an effector of the Sonic Hedgehog (SHH) pathway. Molecular and pharmacological inhibition of SHH reproduced the thyroid defects observed in\n                      <jats:italic toggle=\"yes\">glis3<\/jats:italic>\n                      morphant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Our results demonstrate that\n                      <jats:italic toggle=\"yes\">glis3<\/jats:italic>\n                      , within the SHH pathway, appears to determine the number of endodermal cells committed to a thyroid fate. This is the first evidence of the involvement of Glis3 in TD, thereby expanding the understanding of the genetic basis of thyroid development and CH.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2019.0196","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T07:49:06Z","timestamp":1575445746000},"page":"277-289","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["<i>Glis3<\/i>\n                    as a Critical Regulator of Thyroid Primordium Specification"],"prefix":"10.1177","volume":"30","author":[{"given":"Giuditta","family":"Rurale","sequence":"first","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy."},{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Marelli","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Duminuco","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Persani","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy."},{"name":"Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,2,14]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2003-0028"},{"key":"e_1_3_6_3_2","first-page":"1","article-title":"Murine models for the study of thyroid gland development","volume":"10","author":"De Felice M","year":"2007","unstructured":"De Felice M, , Di Lauro R. 2007. 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