{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:45:20Z","timestamp":1790595920600,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-31227, MOP-42546, MOP-119514"],"award-info":[{"award-number":["MOP-31227, MOP-42546, MOP-119514"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK15070, R01 DK132017-01"],"award-info":[{"award-number":["DK15070, R01 DK132017-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130\u2212\/\u2212 mice exhibit perturbations of thyrocyte cytoskeleton and polarity, and develop postnatal transient growth retardation due to congenital hypothyroidism, leading ultimately to multinodular goiter. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points: week 2 (W2, before visible growth retardation), W4 (at the nadir of growth); and W12 (immediately before full growth recovery). Using gene set enrichment analysis, we compared a defined set of thyroidal genes between Xb130+\/+ and Xb130\u2212\/\u2212 mice to identify differentially enriched gene clusters. At the earliest postnatal stage (W2), the thyroid glands of Xb130\u2212\/\u2212 mice exhibited significantly downregulated gene clusters related to cellular metabolism, which continued to W4. Additionally, mutant thyroids at W4 and W12 showed upregulated gene clusters related to extracellular matrix, angiogenesis, and cell proliferation. At W12, despite nearly normal levels of serum TH and TSH and body size, a significantly large number of gene clusters related to inflammatory response were upregulated. Early postnatal TH deficiency may suppress cellular metabolism within the thyroid gland itself. Upregulation of genes related to extracellular matrix and angiogenesis may promote subsequent thyroid growth. Chronic inflammatory responses may contribute to the pathogenesis of multinodular goiter in later life. Some of the pathoadaptive responses of Xb130\u2212\/\u2212 mice may overlap with those from other mutations causing congenital hypothyroidism.<\/jats:p>","DOI":"10.3390\/cells11060975","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Thyroidal Transcriptomic Profiles of Pathoadaptive Responses to Congenital Hypothyroidism in XB130 Knockout Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Junichi","family":"Sugihara","sequence":"first","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Wong","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6463-8498","authenticated-orcid":false,"given":"Hiroki","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8109-5870","authenticated-orcid":false,"given":"Hae-Ra","family":"Cho","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"},{"name":"Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Wang","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Pediatrics and Committee on Genetics, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9188-8417","authenticated-orcid":false,"given":"Mingyao","family":"Liu","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"},{"name":"Departments of Surgery and Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clp.2017.10.004","article-title":"Congenital Hypothyroidism","volume":"45","author":"Wassner","year":"2018","journal-title":"Clin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1097\/MOP.0b013e32834726a4","article-title":"Genetic causes of congenital hypothyroidism due to dyshormonogenesis","volume":"23","author":"Grasberger","year":"2011","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1089\/10507250360731550","article-title":"Thyroperoxidase gene mutations in congenital goitrous hypothyroidism with total and partial iodide organification defect","volume":"13","author":"Nascimento","year":"2003","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6725","DOI":"10.1074\/jbc.M806893200","article-title":"Activation of dual oxidases Duox1 and Duox2: Differential regulation mediated by camp-dependent protein kinase and protein kinase C-dependent phosphorylation","volume":"284","author":"Rigutto","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1530\/JME-12-0219","article-title":"Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism","volume":"50","author":"Gayral","year":"2013","journal-title":"J. Mol. Endocrinol."},{"key":"ref_6","first-page":"1958","article-title":"Thyroid follicle development requires Smad1\/5- and endothelial cell-dependent basement membrane assembly","volume":"143","author":"Villacorte","year":"2016","journal-title":"Development"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16401","DOI":"10.1074\/jbc.M701684200","article-title":"XB130, a novel adaptor protein for signal transduction","volume":"282","author":"Xu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/onc.2008.447","article-title":"XB130, a tissue-specific adaptor protein that couples the RET\/PTC oncogenic kinase to PI 3-kinase pathway","volume":"28","author":"Lodyga","year":"2009","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.ajpath.2010.11.024","article-title":"XB130, a novel adaptor protein, promotes thyroid tumor growth","volume":"178","author":"Shiozaki","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1089\/thy.2021.0461","article-title":"XB130 plays an essential role in folliculogenesis through mediating interactions between microfilament and microtubule systems in thyrocytes","volume":"32","author":"Wang","year":"2022","journal-title":"Thyroid"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1089\/thy.2021.0195","article-title":"XB130 deficiency causes congenital hypothyroidism in mice due to disorganized apical membrane structure and function of thyrocytes","volume":"31","author":"Wang","year":"2021","journal-title":"Thyroid"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cho, H., Sugihara, J., Wang, Y., Shimizu, H., Xiang, Y., Newbigging, S., Liao, X., Asa, S., Refetoff, S., and Liu, M. (2021). Pathogenesis of multinodular goiter in elderly XB130 deficient mice: Alteration of thyroperoxidase affinity with iodide and hydrogen peroxide. Thyroid.","DOI":"10.1089\/thy.2021.0458"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1902222","DOI":"10.1183\/13993003.02222-2019","article-title":"Potential therapeutic targets for lung repair during human ex vivo lung perfusion","volume":"55","author":"Wong","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhao, J., Wang, Y., Wakeham, A., Hao, Z., Toba, H., Bai, X., Keshavjee, S., Mak, T., and Liu, M. (2014). XB130 deficiency affects tracheal epithelial differentiation during airway repair. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108952"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"30803","DOI":"10.18632\/oncotarget.5062","article-title":"XB130 promotes bronchioalveolar stem cell and Club cell proliferation in airway epithelial repair and regeneration","volume":"6","author":"Toba","year":"2015","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Merico, D., Isserlin, R., Stueker, O., Emili, A., and Bader, G.D. (2010). Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013984"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.12688\/f1000research.9090.1","article-title":"AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations","volume":"5","author":"Kucera","year":"2016","journal-title":"F1000Research"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1089\/thy.2007.0250","article-title":"Thyroid hormone effects on mitochondrial energetics","volume":"18","author":"Harper","year":"2008","journal-title":"Thyroid"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"853","DOI":"10.4161\/cc.5.8.2692","article-title":"Polo-like kinases: A team in control ivision","volume":"5","author":"Medema","year":"2006","journal-title":"Cell Cycle."},{"key":"ref_21","first-page":"e148496","article-title":"Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death","volume":"6","author":"Zhang","year":"2021","journal-title":"JCI Insight"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"730630","DOI":"10.4061\/2011\/730630","article-title":"Looking for the mechanism of action of thyroid hormone","volume":"2011","author":"Tata","year":"2011","journal-title":"J. Thyroid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mce.2013.06.006","article-title":"Thyroid hormones and mitochondria: With a brief look at derivatives and analogues","volume":"379","author":"Cioffi","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1210\/er.2009-0007","article-title":"Molecular aspects of thyroid hormone actions","volume":"31","author":"Cheng","year":"2010","journal-title":"Endocr. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/BF00419598","article-title":"Direct in vitro action of thyroid hormones on mitochondrial RNA-polymerase","volume":"11","author":"Martino","year":"1986","journal-title":"Mol. Biol. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1128\/MCB.19.1.657","article-title":"Direct regulation of mitochondrial RNA synthesis by thyroid hormone","volume":"19","author":"Montoya","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1210\/en.2005-0168","article-title":"Complete inhibition of goiter in mice requires combined gene therapy modification of angiopoietin, vascular endothelial growth factor, and fibroblast growth factor signaling","volume":"146","author":"Ramsden","year":"2005","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1210\/me.2011-1349","article-title":"Phosphatidylinositol 3-kinase-binding protein, PI3KAP\/XB130, is required for cAMP-induced amplification of IGF mitogenic activity in FRTL-5 thyroid cells","volume":"26","author":"Yamanaka","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1677\/joe.0.1660475","article-title":"Angiogenesis in the thyroid gland","volume":"166","author":"Ramsden","year":"2000","journal-title":"J. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1210\/jcem-73-5-1051","article-title":"Inverse relation between iodine intake and thyroid blood flow: Color Doppler flow imaging in euthyroid human","volume":"73","author":"Arntzenius","year":"1991","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1385\/ENDO:11:2:165","article-title":"Inhibition of iodine organification and regulation of follicular size in rat thyroid tissue in vitro","volume":"11","author":"Glaser","year":"1999","journal-title":"Endocrine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nature01320","article-title":"Points of control in inflammation","volume":"420","author":"Nathan","year":"2002","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11319","DOI":"10.3390\/ijms140611319","article-title":"Danger control programs cause tissue injury and remodeling","volume":"14","author":"Hagemann","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2856213","DOI":"10.1155\/2016\/2856213","article-title":"The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is \u201cInflammation\u201d Always Inflammation?","volume":"2016","author":"Kulkarni","year":"2016","journal-title":"Med. Inflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1007\/BF00208480","article-title":"Immunological features of sporadic multinodular goiter","volume":"71","author":"Corrales","year":"1993","journal-title":"Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25420","DOI":"10.18632\/oncotarget.8326","article-title":"XB130 deficiency enhances lipopolysaccharide-induced septic response and acute lung injury","volume":"7","author":"Toba","year":"2016","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/carcin\/bgz042","article-title":"XB130 deficiency enhances carcinogen-induced skin tumorigenesis","volume":"40","author":"Cho","year":"2019","journal-title":"Carcinogenesis"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/6\/975\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:35:30Z","timestamp":1760135730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/6\/975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,12]]},"references-count":37,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cells11060975"],"URL":"https:\/\/doi.org\/10.3390\/cells11060975","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,12]]}}}