{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T21:48:47Z","timestamp":1790459327720,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Ras proteins control a complex intracellular signaling network. Gain-of-function mutations in<jats:italic>RAS<\/jats:italic>genes lead to RASopathy disorders in humans, including Noonan syndrome (NS). NS is the second most common syndromic cause of congenital heart disease. Although conditional expression of the<jats:italic>Nras<jats:sup>G12D\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup>mutation in adult hematopoietic system is leukemogenic, its effects on embryonic development remain unclear. Here, we report that pan-embryonic expression of endogenous<jats:italic>Nras<jats:sup>G12D\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup>by Mox2-Cre in mice caused embryonic lethality from embryonic day (E) 15.5 and developmental defects predominantly in the heart. At E13.5,<jats:italic>Nras<jats:sup>G12D\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup><jats:italic>; Mox2<jats:sup>Cre\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup>embryos displayed a moderate expansion of hematopoietic stem and progenitor cells without a significant impact on erythroid differentiation in the fetal liver. Importantly, the mutant embryos exhibited cardiac malformations resembling human congenital cardiac defects seen in NS patients, including ventricular septal defects, double outlet right ventricle, the hypertrabeculation\/thin myocardium, and pulmonary valve stenosis. The mutant heart showed dysregulation of ERK, BMP, and Wnt pathways, crucial signaling pathways for cardiac development. Endothelial\/endocardial-specific expression of<jats:italic>Nras<jats:sup>G12D\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup>caused the cardiac morphological defects and embryonic lethality as observed in<jats:italic>Nras<jats:sup>G12D\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup><jats:italic>; Mox2<jats:sup>Cre\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup>mutants, but myocardial-specific expression of<jats:italic>Nras<jats:sup>G12D\/<\/jats:sup><\/jats:italic><jats:sup>+<\/jats:sup>did not. Thus, oncogenic<jats:italic>Nras<jats:sup>G12D<\/jats:sup><\/jats:italic>mutation may not be compatible with embryonic survival.<\/jats:p>","DOI":"10.3389\/fcell.2021.633661","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T11:24:24Z","timestamp":1613215464000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Embryonic Expression of NrasG 12 D Leads to Embryonic Lethality and Cardiac Defects"],"prefix":"10.3389","volume":"9","author":[{"given":"Xiaona","family":"You","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung-Jeom","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunjin","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhi","family":"Sang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Damnernsawad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngsook","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/ejhg.2017.65","article-title":"Genotype and phenotype spectrum of NRAS germline variants.","volume":"25","author":"Altmuller","year":"2017","journal-title":"Eur. 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