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R-spondins are secreted factors and potent Wnt agonists that in part regulate stem cell proliferation. Our data show that Rspo3 is markedly downregulated in Nkx2-5 mutants and that Rspo3 expression is regulated by Nkx2-5. Conditional inactivation of Rspo3 in the Isl1 lineage resulted in embryonic lethality secondary to impaired development of SHF. More importantly, we find that Wnt signaling is significantly attenuated in Nkx2-5 mutants and that enhancing Wnt\/\u03b2-catenin signaling by pharmacological treatment or by transgenic expression of Rspo3 rescues the SHF defects in the conditional Nkx2-5+\/\u2212 mutants. We have identified a previously unrecognized genetic link between Nkx2-5 and Wnt signaling that supports continued cardiac growth and proliferation during development. Identification of Rspo3 in cardiac development provides a new paradigm in temporal regulation of Wnt signaling by cardiac-specific transcription factors.<\/jats:p>","DOI":"10.1242\/dev.103416","type":"journal-article","created":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T11:19:14Z","timestamp":1406027954000},"page":"2959-2971","source":"Crossref","is-referenced-by-count":78,"title":["Nkx2-5 regulates cardiac growth through modulation of Wnt signaling by R-spondin3"],"prefix":"10.1242","volume":"141","author":[{"given":"Linda","family":"Cambier","sequence":"first","affiliation":[{"name":"Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Plate","sequence":"additional","affiliation":[{"name":"Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry M.","family":"Sucov","sequence":"additional","affiliation":[{"name":"Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Pashmforoush","sequence":"additional","affiliation":[{"name":"Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021052800034630400_DEV103416C1","doi-asserted-by":"publisher","first-page":"9319","DOI":"10.1073\/pnas.0701212104","article-title":"Canonical Wnt signaling functions in second heart field to promote right ventricular growth","volume":"104","author":"Ai","year":"2007","journal-title":"Proc. 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