{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:48:07Z","timestamp":1792280887360,"version":"4.4.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,3,28]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart. Although human mutation of\n              <jats:italic>NKX2-5<\/jats:italic>\n              is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>In this study, we circumvented these limitations by atrial-restricted deletion of Nkx2-5.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Method and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Atrial-specific Nkx2-5 mutants died shortly after birth with hyperplastic working myocytes and conduction system including two nodes and internodal tracts. Multicolor reporter analysis revealed that Nkx2-5\u2013null cardiomyocytes displayed clonal proliferative activity throughout the atria, indicating the suppressive role of Nkx2-5 in cardiomyocyte proliferation after chamber ballooning stages. Transcriptome analysis revealed that aberrant activation of Notch signaling underlies hyperproliferation of mutant cardiomyocytes, and forced activation of Notch signaling recapitulates hyperproliferation of working myocytes but not the conduction system.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Collectively, these data suggest that Nkx2-5 regulates the proliferation of atrial working and conduction myocardium in coordination with Notch pathway.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.114.303219","type":"journal-article","created":{"date-parts":[[2014,2,22]],"date-time":"2014-02-22T07:32:35Z","timestamp":1393054355000},"page":"1103-1113","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":62,"title":["Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System"],"prefix":"10.1161","volume":"114","author":[{"given":"Yasuhiro","family":"Nakashima","sequence":"first","affiliation":[{"name":"From the Department of Molecular Cell and Developmental Biology (Y.N., D.A.Y., H.N., A.J., M.P., A.N.), Departments of Pediatrics and Molecular Cell and Integrative Physiology, David Geffen School of Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive Cancer..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana A.","family":"Yanez","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Cell and Developmental Biology (Y.N., D.A.Y., H.N., A.J., M.P., A.N.), Departments of Pediatrics and Molecular Cell and Integrative Physiology, David Geffen School of Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive Cancer..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlin","family":"Touma","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Cell and Developmental Biology (Y.N., D.A.Y., H.N., A.J., M.P., A.N.), Departments of Pediatrics and Molecular Cell and Integrative Physiology, David Geffen School of Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive 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Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive Cancer..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Jordan","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Cell and Developmental Biology (Y.N., D.A.Y., H.N., A.J., M.P., A.N.), Departments of Pediatrics and Molecular Cell and Integrative Physiology, David Geffen School of Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive 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Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive Cancer..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Nakano","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Cell and Developmental Biology (Y.N., D.A.Y., H.N., A.J., M.P., A.N.), Departments of Pediatrics and Molecular Cell and Integrative Physiology, David Geffen School of Medicine (M.T.), Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (H.N., M.P., A.N.), Department of Physiology, David Geffen School of Medicine (M.C.J., K.P.R.), Molecular Biology Institute (M.P.), Institute of Genomics and Proteomics (M.P.), and Jonsson Comprehensive 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