{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:14:36Z","timestamp":1784873676229,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pbio.3002598","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000}}],"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003762","name":"Institut Pasteur","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"INSERM","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ANR","award":["ANR-10-IAHU-01"],"award-info":[{"award-number":["ANR-10-IAHU-01"]}]},{"name":"ANR","award":["ANR-10-LABX-73-01 REVIVE"],"award-info":[{"award-number":["ANR-10-LABX-73-01 REVIVE"]}]},{"DOI":"10.13039\/501100001961","name":"AXA Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001961","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ANR","award":["ANR-18-CE15-0025-03"],"award-info":[{"award-number":["ANR-18-CE15-0025-03"]}]},{"DOI":"10.13039\/100016913","name":"MSDAVENIR","doi-asserted-by":"publisher","award":["Devo-Decode"],"award-info":[{"award-number":["Devo-Decode"]}],"id":[{"id":"10.13039\/100016913","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PROCEED project ERA PerMED joint Translational Call Initiative","award":["01KU1919"],"award-info":[{"award-number":["01KU1919"]}]},{"DOI":"10.13039\/100010447","name":"German Center for Cardiovascular Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Institut Pasteur PPU"},{"name":"FRM","award":["FDT202106012984"],"award-info":[{"award-number":["FDT202106012984"]}]},{"name":"Bettencourt Schueller foundation"},{"name":"EURIP","award":["ANR-17-EURE-0012"],"award-info":[{"award-number":["ANR-17-EURE-0012"]}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>The TGF\u03b2 secreted factor NODAL is a major left determinant required for the asymmetric morphogenesis of visceral organs, including the heart. Yet, when this signaling is absent, shape asymmetry, for example of the embryonic heart loop, is not fully abrogated, indicating that there are other factors regulating left\u2013right patterning. Here, we used a tailored transcriptomic approach to screen for genes asymmetrically expressed in the field of heart progenitors. We thus identify <jats:italic>Notch3<\/jats:italic> as a novel left-enriched gene and validate, by quantitative in situ hybridization, its transient asymmetry in the lateral plate mesoderm and node crown, overlapping with <jats:italic>Nodal<\/jats:italic>. In mutant embryos, we analyzed the regulatory hierarchy and demonstrate that <jats:italic>Nodal<\/jats:italic> in the lateral plate mesoderm amplifies <jats:italic>Notch3<\/jats:italic> asymmetric expression. The function of <jats:italic>Notch3<\/jats:italic> was uncovered in an allelic series of mutants. In single neonate mutants, we observe that <jats:italic>Notch3<\/jats:italic> is required with partial penetrance for ventricle thickness, septation and aortic valve, in addition to its known role in coronary arteries. In compound mutants, we reveal that <jats:italic>Notch3<\/jats:italic> acts as a genetic modifier of heart looping direction and shape defects in <jats:italic>Nodal<\/jats:italic> mutants. Whereas <jats:italic>Notch3<\/jats:italic> was previously mainly associated with the CADASIL syndrome, our observations in the mouse and a human cohort support a novel role in congenital heart defects and laterality defects.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002598","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T20:37:10Z","timestamp":1743453430000},"page":"e3002598","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Notch3 is an asymmetric gene and a modifier of heart looping defects in Nodal mouse mutants"],"prefix":"10.1371","volume":"23","author":[{"given":"Tobias Holm","family":"B\u00f8nnelykke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Amandine","family":"Chabry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeline","family":"Perthame","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Dombrowsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Dittrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Phillip","family":"Hitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Desgrange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-2617","authenticated-orcid":true,"given":"Sigol\u00e8ne M.","family":"Meilhac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"issue":"1","key":"pbio.3002598.ref001","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/oxfordjournals.jhered.a106870","article-title":"Visceral inversion and associated anomalies in the mouse","volume":"50","author":"K Hummel","year":"1959","journal-title":"J Hered"},{"issue":"6578","key":"pbio.3002598.ref002","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/381151a0","article-title":"Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos","volume":"381","author":"C Meno","year":"1996","journal-title":"Nature"},{"issue":"10","key":"pbio.3002598.ref003","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1002\/ajmg.a.36695","article-title":"Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology","author":"AE Lin","year":"2014","journal-title":"Am J Med Genet A"},{"issue":"7","key":"pbio.3002598.ref004","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2183\/pjab.96.021","article-title":"Molecular and cellular basis of left-right asymmetry in vertebrates","volume":"96","author":"H Hamada","year":"2020","journal-title":"Proc Jpn Acad Ser B Phys Biol Sci"},{"issue":"6","key":"pbio.3002598.ref005","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0092-8674(00)81705-5","article-title":"Randomization of left\u2013right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein","volume":"95","author":"S Nonaka","year":"1998","journal-title":"Cell"},{"issue":"18","key":"pbio.3002598.ref006","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1101\/gad.1016202","article-title":"Nodal activity in the node governs left-right asymmetry","volume":"16","author":"J Brennan","year":"2002","journal-title":"Genes Dev"},{"issue":"1","key":"pbio.3002598.ref007","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0092-8674(03)00511-7","article-title":"Two populations of node monocilia initiate left-right asymmetry in the mouse","volume":"114","author":"J McGrath","year":"2003","journal-title":"Cell"},{"issue":"6627","key":"pbio.3002598.ref008","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1126\/science.abq8148","article-title":"Immotile cilia mechanically sense the direction of fluid flow for left-right determination","volume":"379","author":"T Katoh","year":"2023","journal-title":"Science"},{"issue":"11","key":"pbio.3002598.ref009","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/ng.3376","article-title":"MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates","volume":"47","author":"A Guimier","year":"2015","journal-title":"Nat Genet"},{"issue":"1","key":"pbio.3002598.ref010","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41588-021-00970-4","article-title":"Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates","volume":"54","author":"E Szenker-Ravi","year":"2022","journal-title":"Nat Genet"},{"issue":"6613","key":"pbio.3002598.ref011","doi-asserted-by":"crossref","first-page":"eabl3921","DOI":"10.1126\/science.abl3921","article-title":"Pitx2 patterns an accelerator-brake mechanical feedback through latent TGF\u03b2 to rotate the gut","volume":"377","author":"BD Sanketi","year":"2022","journal-title":"Science"},{"issue":"4","key":"pbio.3002598.ref012","doi-asserted-by":"crossref","first-page":"413-431.e6","DOI":"10.1016\/j.devcel.2020.10.008","article-title":"Transient nodal signaling in left precursors coordinates opposed asymmetries shaping the heart loop","volume":"55","author":"A Desgrange","year":"2020","journal-title":"Dev Cell"},{"issue":"10","key":"pbio.3002598.ref013","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1242\/dev.128.10.1831","article-title":"Genetic dissection of nodal function in patterning the mouse embryo","volume":"128","author":"LA Lowe","year":"2001","journal-title":"Development"},{"issue":"1","key":"pbio.3002598.ref014","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0012-1606(02)00121-5","article-title":"Left\u2013right patterning of the mouse lateral plate requires nodal produced in the node","volume":"256","author":"Y Saijoh","year":"2003","journal-title":"Dev Biol"},{"issue":"12","key":"pbio.3002598.ref015","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.1002\/dvdy.21665","article-title":"Broad mesodermal and endodermal deletion of Nodal at postgastrulation stages results solely in left\/right axial defects","volume":"237","author":"A Kumar","year":"2008","journal-title":"Dev Dynam"},{"issue":"22","key":"pbio.3002598.ref016","doi-asserted-by":"crossref","first-page":"dev162776","DOI":"10.1242\/dev.162776","article-title":"Left-right asymmetry in heart development and disease: forming the right loop","volume":"145","author":"A Desgrange","year":"2018","journal-title":"Development"},{"key":"pbio.3002598.ref017","doi-asserted-by":"crossref","first-page":"e28951","DOI":"10.7554\/eLife.28951","article-title":"A predictive model of asymmetric morphogenesis from 3D reconstructions of mouse heart looping dynamics","volume":"6","author":"J Le Garrec","year":"2017","journal-title":"eLife"},{"issue":"6533","key":"pbio.3002598.ref018","doi-asserted-by":"crossref","first-page":"eabb2986","DOI":"10.1126\/science.abb2986","article-title":"Characterization of a common progenitor pool of the epicardium and myocardium","volume":"371","author":"RCV Tyser","year":"2021","journal-title":"Science"},{"issue":"10","key":"pbio.3002598.ref019","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1161\/CIRCRESAHA.112.271247","article-title":"Asymmetric fate of the posterior part of the second heart field results in unexpected left\/right contributions to both poles of the heart","volume":"111","author":"JN Dom\u00ednguez","year":"2012","journal-title":"Circ Res"},{"issue":"1","key":"pbio.3002598.ref020","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1006\/dbio.1999.9594","article-title":"Smad5 is essential for left\u2013right asymmetry in mice","volume":"219","author":"H Chang","year":"2000","journal-title":"Dev Biol"},{"issue":"14","key":"pbio.3002598.ref021","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1242\/dev.018986","article-title":"BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment","volume":"135","author":"N Mine","year":"2008","journal-title":"Development"},{"issue":"21","key":"pbio.3002598.ref022","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1101\/gad.1682108","article-title":"BMP\/SMAD1 signaling sets a threshold for the left\/right pathway in lateral plate mesoderm and limits availability of SMAD4","volume":"22","author":"M Furtado","year":"2008","journal-title":"Genes Dev"},{"issue":"22","key":"pbio.3002598.ref023","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1016\/j.cub.2009.09.057","article-title":"An Hh-dependent pathway in lateral plate mesoderm enables the generation of left\/right asymmetry","volume":"19","author":"CD Tsiairis","year":"2009","journal-title":"Curr Biol"},{"issue":"1","key":"pbio.3002598.ref024","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1242\/dev.00176","article-title":"Node and midline defects are associated with left-right development in Delta1 mutant embryos","volume":"130","author":"GKH Przemeck","year":"2003","journal-title":"Development"},{"issue":"10","key":"pbio.3002598.ref025","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1101\/gad.1084703","article-title":"Notch signaling regulates left-right asymmetry determination by inducing Nodal expression","volume":"17","author":"LT Krebs","year":"2003","journal-title":"Genes Dev"},{"issue":"10","key":"pbio.3002598.ref026","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1101\/gad.1084403","article-title":"Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos","volume":"17","author":"A Raya","year":"2003","journal-title":"Genes Dev"},{"issue":"24","key":"pbio.3002598.ref027","doi-asserted-by":"crossref","first-page":"5425","DOI":"10.1242\/dev.02149","article-title":"Wnt3a links left-right determination with segmentation and anteroposterior axis elongation","volume":"132","author":"M Nakaya","year":"2005","journal-title":"Development"},{"issue":"2","key":"pbio.3002598.ref028","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ydbio.2013.05.011","article-title":"Wnt signaling regulates left\u2013right axis formation in the node of mouse embryos","volume":"380","author":"K Kitajima","year":"2013","journal-title":"Dev Biol"},{"issue":"5","key":"pbio.3002598.ref029","doi-asserted-by":"crossref","first-page":"439-452.e4","DOI":"10.1016\/j.devcel.2017.02.010","article-title":"A Wnt5 activity asymmetry and intercellular signaling via PCP proteins polarize node cells for left-right symmetry breaking","volume":"40","author":"K Minegishi","year":"2017","journal-title":"Dev Cell"},{"issue":"11","key":"pbio.3002598.ref030","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41569-018-0100-2","article-title":"Notch and interacting signalling pathways in cardiac development, disease, and regeneration","volume":"15","author":"D MacGrogan","year":"2018","journal-title":"Nat Rev Cardiol"},{"issue":"3","key":"pbio.3002598.ref031","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0925-4773(95)00451-3","article-title":"Complementary and combinatorial patterns of Notch gene family expression during early mouse development","volume":"53","author":"R Williams","year":"1995","journal-title":"Mech Dev"},{"issue":"27","key":"pbio.3002598.ref032","doi-asserted-by":"crossref","first-page":"10921","DOI":"10.1073\/pnas.1121236109","article-title":"Wnt\/\u03b2-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells","volume":"109","author":"A Klaus","year":"2012","journal-title":"Proc Natl Acad Sci"},{"issue":"8","key":"pbio.3002598.ref033","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/ncb1906","article-title":"A regulatory pathway involving Notch1\/beta-catenin\/Isl1 determines cardiac progenitor cell fate","volume":"11","author":"C Kwon","year":"2009","journal-title":"Nat Cell Biol"},{"key":"pbio.3002598.ref034","first-page":"2020.02.20.958348","article-title":"Notch signaling commits mesoderm to the cardiac lineage [Internet]","author":"ES Bardot","year":"2020","journal-title":"bioRxiv"},{"issue":"7705","key":"pbio.3002598.ref035","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41586-018-0110-6","article-title":"Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation","volume":"557","author":"G Del Monte-Nieto","year":"2018","journal-title":"Nature"},{"issue":"1","key":"pbio.3002598.ref036","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1101\/gad.276304","article-title":"Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation","volume":"18","author":"LA Timmerman","year":"2004","journal-title":"Genes Dev"},{"issue":"10","key":"pbio.3002598.ref037","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1161\/CIRCRESAHA.115.308077","article-title":"Sequential ligand-dependent Notch signaling activation regulates valve primordium formation and morphogenesis","volume":"118","author":"D MacGrogan","year":"2016","journal-title":"Circ Res"},{"issue":"3","key":"pbio.3002598.ref038","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/gene.10241","article-title":"Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation","volume":"37","author":"LT Krebs","year":"2003","journal-title":"Genesis"},{"key":"pbio.3002598.ref039","doi-asserted-by":"crossref","first-page":"e10036","DOI":"10.7554\/eLife.10036","article-title":"Pericytes are progenitors for coronary artery smooth muscle","volume":"4","author":"K Volz","year":"2015","journal-title":"eLife"},{"issue":"22","key":"pbio.3002598.ref040","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1101\/gad.308904","article-title":"Notch3 is required for arterial identity and maturation of vascular smooth muscle cells","volume":"18","author":"V Domenga","year":"2004","journal-title":"Genes Dev"},{"issue":"5","key":"pbio.3002598.ref041","doi-asserted-by":"crossref","first-page":"e37365","DOI":"10.1371\/journal.pone.0037365","article-title":"Notch2 and Notch3 function together to regulate vascular smooth muscle development","volume":"7","author":"Q Wang","year":"2012","journal-title":"PLoS One"},{"issue":"9","key":"pbio.3002598.ref042","doi-asserted-by":"crossref","first-page":"1159-1174.e5","DOI":"10.1016\/j.devcel.2024.03.005","article-title":"Villus myofibroblasts are developmental and adult progenitors of mammalian gut lymphatic musculature","volume":"59","author":"BD Sanketi","year":"2024","journal-title":"Dev Cell"},{"issue":"9090","key":"pbio.3002598.ref043","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/S0140-6736(97)08083-5","article-title":"Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients","volume":"350","author":"A Joutel","year":"1997","journal-title":"Lancet"},{"issue":"1","key":"pbio.3002598.ref044","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/jcbfm.2015.71","article-title":"Genetic factors in cerebral small vessel disease and their impact on stroke and dementia","volume":"36","author":"C Haffner","year":"2016","journal-title":"J Cereb Blood Flow Metab"},{"issue":"12","key":"pbio.3002598.ref045","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1002\/stem.547","article-title":"Notch3 null mutation in mice causes muscle hyperplasia by repetitive muscle regeneration","volume":"28","author":"T Kitamoto","year":"2010","journal-title":"Stem Cells"},{"issue":"1","key":"pbio.3002598.ref046","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1083\/jcb.201307046","article-title":"Notch3 marks clonogenic mammary luminal progenitor cells in vivo","volume":"203","author":"D Lafkas","year":"2013","journal-title":"J Cell Biol"},{"issue":"49","key":"pbio.3002598.ref047","doi-asserted-by":"crossref","first-page":"11867","DOI":"10.1523\/JNEUROSCI.0001-17.2017","article-title":"Area-specific regulation of quiescent neural stem cells by Notch3 in the adult mouse subependymal zone","volume":"37","author":"H Kawai","year":"2017","journal-title":"J Neurosci"},{"issue":"10","key":"pbio.3002598.ref048","doi-asserted-by":"crossref","first-page":"dev161034","DOI":"10.1242\/dev.161034","article-title":"Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signalling cascade in the vertebrate adult brain","volume":"145","author":"E Than-Trong","year":"2018","journal-title":"Development"},{"key":"pbio.3002598.ref049","article-title":"NOTCH3-related lateral Meningocele syndrome.","volume-title":"GeneReviews\u00ae","author":"R Ejaz","year":"2016"},{"issue":"11","key":"pbio.3002598.ref050","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1101\/gad.14.11.1343","article-title":"Notch signaling is essential for vascular morphogenesis in mice","volume":"14","author":"LT Krebs","year":"2000","journal-title":"Genes Dev"},{"key":"pbio.3002598.ref051","first-page":"2022.12.26.521947","article-title":"Molecular characterization of left-right symmetry breaking in the mouse embryo [Internet]","author":"RCV Tyser","year":"2022","journal-title":"bioRxiv"},{"key":"pbio.3002598.ref052","first-page":"2023.04.21.537827","article-title":"Spatial transcriptome profiling uncovers metabolic regulation of left-right patterning [Internet]","author":"H Yagi","year":"2023","journal-title":"bioRxiv"},{"issue":"11","key":"pbio.3002598.ref053","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.mod.2004.06.002","article-title":"Asymmetric Nodal expression in the mouse is governed by the combinatorial activities of two distinct regulatory elements","volume":"121","author":"SD Vincent","year":"2004","journal-title":"Mech Dev"},{"issue":"6750","key":"pbio.3002598.ref054","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/45797","article-title":"Function of Rieger syndrome gene in left-right asymmetry and craniofacial development","volume":"401","author":"MF Lu","year":"1999","journal-title":"Nature"},{"issue":"5","key":"pbio.3002598.ref055","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"S Richards","year":"2015","journal-title":"Genet Med"},{"issue":"3","key":"pbio.3002598.ref056","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0092-8674(00)81475-0","article-title":"Pitx2 participates in the late phase of the pathway controlling left-right asymmetry","volume":"94","author":"ME Piedra","year":"1998","journal-title":"Cell"},{"issue":"1","key":"pbio.3002598.ref057","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S1097-2765(00)80401-3","article-title":"Left\u2013right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2","volume":"5","author":"Y Saijoh","year":"2000","journal-title":"Mol Cell"},{"issue":"11","key":"pbio.3002598.ref058","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1242\/dev.128.11.2039","article-title":"Regulation of left-right asymmetry by thresholds of Pitx2c activity","volume":"128","author":"C Liu","year":"2001","journal-title":"Development"},{"issue":"2","key":"pbio.3002598.ref059","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/cvr\/cvr314","article-title":"Pitx2 confers left morphological, molecular, and functional identity to the sinus venosus myocardium","volume":"93","author":"G Ammirabile","year":"2012","journal-title":"Cardiovasc Res"},{"issue":"1","key":"pbio.3002598.ref060","doi-asserted-by":"crossref","first-page":"15022","DOI":"10.1038\/s41598-023-42010-7","article-title":"Left ventricular hypertrophy and metabolic resetting in the Notch3-deficient adult mouse heart","volume":"13","author":"F Del Gaudio","year":"2023","journal-title":"Sci Rep"},{"issue":"3","key":"pbio.3002598.ref061","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1083\/jcb.200905105","article-title":"Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1","volume":"187","author":"K Watanabe","year":"2009","journal-title":"J Cell Biol"},{"issue":"1","key":"pbio.3002598.ref062","doi-asserted-by":"crossref","first-page":"101937","DOI":"10.1016\/j.gde.2022.101937","article-title":"The genetic landscape of cardiovascular left\u2013right patterning defects","volume":"75","author":"J Wells","year":"2022","journal-title":"Curr Opin Genet Dev"},{"issue":"6","key":"pbio.3002598.ref063","doi-asserted-by":"crossref","first-page":"848","DOI":"10.15252\/emmm.201404399","article-title":"Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy","volume":"7","author":"T Pippucci","year":"2015","journal-title":"EMBO Mol Med"},{"issue":"1","key":"pbio.3002598.ref064","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ydbio.2004.06.004","article-title":"Multiple roles for Nodal in the epiblast of the mouse embryo in the establishment of anterior-posterior patterning","volume":"273","author":"C Lu","year":"2004","journal-title":"Dev Biol"},{"issue":"3","key":"pbio.3002598.ref065","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/90074","article-title":"Functional analysis of secreted and transmembrane proteins critical to mouse development","volume":"28","author":"KJ Mitchell","year":"2001","journal-title":"Nat Genet"},{"issue":"21","key":"pbio.3002598.ref066","doi-asserted-by":"crossref","first-page":"2217-2234.e8","DOI":"10.1016\/j.devcel.2023.09.006","article-title":"Identification of Greb1l as a genetic determinant of crisscross heart in mice showing torsion of the heart tube by shortage of progenitor cells","volume":"58","author":"S Bernheim","year":"2023","journal-title":"Dev Cell"},{"issue":"11","key":"pbio.3002598.ref067","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1038\/nprot.2015.085","article-title":"Advanced CUBIC protocols for whole-brain and whole-body clearing and imaging","volume":"10","author":"EA Susaki","year":"2015","journal-title":"Nat Protoc"},{"issue":"7","key":"pbio.3002598.ref068","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nmeth.2075","article-title":"Icy: an open bioimage informatics platform for extended reproducible research","volume":"9","author":"F de Chaumont","year":"2012","journal-title":"Nat Methods"},{"issue":"4","key":"pbio.3002598.ref069","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in ingenuity pathway analysis","volume":"30","author":"A Kr\u00e4mer","year":"2014","journal-title":"Bioinformatics"},{"key":"pbio.3002598.ref070","first-page":"2122","article-title":"A step-by-step workflow for low-level analysis of single-cell RNA-seq data with Bioconductor","volume":"5","author":"ATL Lun","year":"2016","journal-title":"F1000Res"},{"issue":"7","key":"pbio.3002598.ref071","doi-asserted-by":"crossref","first-page":"1888-1902.e21","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"T Stuart","year":"2019","journal-title":"Cell"},{"issue":"1","key":"pbio.3002598.ref072","doi-asserted-by":"crossref","first-page":"7960","DOI":"10.1038\/s41467-022-35691-7","article-title":"Single-cell transcriptomic analysis identifies murine heart molecular features at embryonic and neonatal stages","volume":"13","author":"W Feng","year":"2022","journal-title":"Nat Commun"},{"key":"pbio.3002598.ref073","first-page":"4","article-title":"The segmental approach to diagnosis in congenital heart disease","volume":"8","author":"R Van Praagh","year":"1972","journal-title":"Birth Defects Orig Artic Ser"},{"issue":"7","key":"pbio.3002598.ref074","doi-asserted-by":"crossref","first-page":"e1009679","DOI":"10.1371\/journal.pgen.1009679","article-title":"Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease","volume":"17","author":"E Audain","year":"2021","journal-title":"PLoS Genet"},{"issue":"12","key":"pbio.3002598.ref075","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","article-title":"Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria","volume":"109","author":"V Pejaver","year":"2022","journal-title":"Am J Hum Genet"},{"issue":"12","key":"pbio.3002598.ref076","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1007\/s00439-016-1727-x","article-title":"Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways","volume":"135","author":"EM Hagen","year":"2016","journal-title":"Hum Genet"},{"issue":"12","key":"pbio.3002598.ref077","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1002\/humu.24132","article-title":"Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and\/or heterotaxy","volume":"41","author":"H Liu","year":"2020","journal-title":"Hum Mutat"},{"issue":"1","key":"pbio.3002598.ref078","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1186\/s13023-022-02515-2","article-title":"A multi-disciplinary, comprehensive approach to management of children with heterotaxy","volume":"17","author":"TG Saba","year":"2022","journal-title":"Orphanet J Rare Dis"}],"updated-by":[{"DOI":"10.1371\/journal.pbio.3002598","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000}}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3002598","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T20:07:58Z","timestamp":1744315678000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3002598"}},"subtitle":[],"editor":[{"given":"Mary C.","family":"Mullins,","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":78,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3002598","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pbio.3002598","asserted-by":"object"}]},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,31]]}}}