{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T17:52:03Z","timestamp":1793987523598,"version":"4.8.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Short stature homeobox (\n                    <jats:italic>SHOX)<\/jats:italic>\n                    and its close paralogue SHOX2 are important transcriptional regulators of developmental processes. To understand how they function both individually and as an ensemble, we examined their mutual interdependence using zebrafish as a model. As both genes maintain important roles in various tissues, we assessed their expression patterns in the whole embryo as well as separately in fins, heart and brain. Fibroblast growth factor receptor 3 (\n                    <jats:italic>FGFR3)<\/jats:italic>\n                    is a direct target of SHOX, and\n                    <jats:italic>FGFR3<\/jats:italic>\n                    mutations cause achondroplasia, a condition treatable with C-type natriuretic peptide (CNP) analogues. Building on this knowledge, we investigated how altered\n                    <jats:italic>shox<\/jats:italic>\n                    and\n                    <jats:italic>shox2<\/jats:italic>\n                    expression relates to\n                    <jats:italic>fgfr3<\/jats:italic>\n                    expression and the natriuretic peptide family (\n                    <jats:italic>nppa<\/jats:italic>\n                    ,\n                    <jats:italic>nppb<\/jats:italic>\n                    ,\n                    <jats:italic>nppc<\/jats:italic>\n                    ) in zebrafish. Here, we demonstrate that\n                    <jats:italic>shox<\/jats:italic>\n                    and\n                    <jats:italic>shox2<\/jats:italic>\n                    mutually regulate each other\u2019s expression in a tissue-specific manner. In brain and whole embryos their effects are additive and synergistic, while in fins and heart their combined actions become partially antagonistic. Distinct tissue-specific effects of\n                    <jats:italic>shox<\/jats:italic>\n                    and\n                    <jats:italic>shox2<\/jats:italic>\n                    were also noted on natriuretic peptide gene activity. In the fin,\n                    <jats:italic>shox<\/jats:italic>\n                    knockdown reduces\n                    <jats:italic>nppc<\/jats:italic>\n                    transcript levels, whereas in heart tissue, deficiency of\n                    <jats:italic>shox<\/jats:italic>\n                    and\n                    <jats:italic>shox2<\/jats:italic>\n                    , particularly in the double knockdown, results in an increased expression of\n                    <jats:italic>nppb<\/jats:italic>\n                    , a known marker for cardiac stress. We also show that shox2 deficiency increases\n                    <jats:italic>fgfr3<\/jats:italic>\n                    levels, which are reduced by CNP treatment. These results in zebrafish may have implications for other vertebrates, including humans with SHOX deficiency, who should be monitored for cardiac disease in later life, and those who have an inadequate response to growth hormone may profit from CNP therapy.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1803846","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:12:26Z","timestamp":1776399146000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Linking shox\/shox2 deficiency with fgfr3 gain-of-function and natriuretic peptides"],"prefix":"10.3389","volume":"17","author":[{"given":"Sandra","family":"Hoffmann","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg\/Mannheim","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Diebold","sequence":"additional","affiliation":[{"name":"Molecular Cardiology, Clinic for Internal Medicine II, University Hospital Ulm","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Roeth","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]},{"name":"Expression & Spatial Profiling Core Facility, Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"L\u00f6wen","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Mellein","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]},{"name":"Expression & Spatial Profiling Core Facility, Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Just","sequence":"additional","affiliation":[{"name":"Molecular Cardiology, Clinic for Internal Medicine II, University Hospital Ulm","place":["Ulm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun A.","family":"Rappold","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Hospital Heidelberg","place":["Heidelberg, Germany"]},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg\/Mannheim","place":["Heidelberg, 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