{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T22:20:07Z","timestamp":1776982807913,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft DFG","award":["SCHU1600\/6-1"],"award-info":[{"award-number":["SCHU1600\/6-1"]}]},{"name":"Deutsche Forschungsgemeinschaft DFG","award":["453989101"],"award-info":[{"award-number":["453989101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sprouty-related proteins with enabled\/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain (SPREDs) are negative regulators of the Ras\/MAPK signaling pathway and are known to modulate developmental and endocrine processes. While the roles of SPRED1 and SPRED2 are increasingly understood, the physiological relevance of SPRED3 remains elusive. To elucidate its function, we generated SPRED3 knockout (KO) mice and performed phenotypic, molecular, and hormonal analyses. SPRED3-deficient mice exhibited growth retardation and a non-Mendelian genotype distribution. X-Gal staining revealed Spred3 promoter activity in the thyroid, adrenal gland, pituitary, cerebral cortex, and kidney. Hormonal profiling identified elevated thyroid-stimulating hormone (TSH) and reduced thyroxine (T4) levels, indicating primary hypothyroidism. Thyroidal extracellular signal-regulated kinase (ERK) signaling was mildly reduced in SPRED3 KO mice, and immunoblotting revealed altered expression of autophagy regulators, including reduced sequestosome 1 (p62), increased autophagy-related gene 5 (ATG5), as well as an elevated microtubule-associated protein 1 light chain 3 (LC3) II\/I ratio and a decreased pBeclin\/Beclin ratio in SPRED3 KO mice. Our findings indicate that SPRED3 is involved in thyroidal homeostasis and plays a regulatory role in autophagy processes within the thyroid gland.<\/jats:p>","DOI":"10.3390\/ijms26157660","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T09:56:42Z","timestamp":1754647002000},"page":"7660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss of SPRED3 Causes Primary Hypothyroidism and Alters Thyroidal Expression of Autophagy Regulators LC3, p62, and ATG5 in Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Celine","family":"Dogan","sequence":"first","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Haas","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Holzapfel","sequence":"additional","affiliation":[{"name":"Institute of Experimental Biomedicine I, University Hospital Wuerzburg, Rudolf Virchow Center, University of Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Hepbasli","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Ullrich","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases, University Clinic Wuerzburg, Josef-Schneider-Strasse 2, 97080 Wuerzburg, Germany"},{"name":"Center for Medical Informatics, University Clinic Wuerzburg, Schweinfurter Strasse 4, 97080 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4448-1382","authenticated-orcid":false,"given":"Michael R.","family":"B\u00f6sl","sequence":"additional","affiliation":[{"name":"Institute of Experimental Biomedicine I, University Hospital Wuerzburg, Rudolf Virchow Center, University of Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Abe\u00dfer","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4475-0412","authenticated-orcid":false,"given":"Kai","family":"Schuh","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sina","family":"Gredy","sequence":"additional","affiliation":[{"name":"Institute of Physiology I, University Wuerzburg, Roentgenring 9, 97070 Wuerzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/35088082","article-title":"Spred is a Sprouty-related suppressor of Ras signalling","volume":"412","author":"Wakioka","year":"2001","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.bbamcr.2010.12.012","article-title":"The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation","volume":"1813","author":"Plotnikov","year":"2011","journal-title":"Biochim. 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