{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:27:19Z","timestamp":1781821639866,"version":"3.54.5"},"reference-count":13,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,4,5]]},"abstract":"\n Background<\/jats:title>\n \n Binding of Slit ligands to their Robo receptors regulates signaling pathways that are important for heart development. Genetic variants in\n ROBO1<\/jats:italic>\n and\n ROBO4<\/jats:italic>\n have been linked to congenital heart defects in humans. These defects are recapitulated in mouse models with ubiquitous deletions of the Slit ligands or Robo receptors and include additional heart defects not currently linked to SLIT or ROBO mutations in humans. Given the broad expression patterns of these genes, the question remains open which tissue\u2010specific ligand\u2010receptor interactions are important for the correct development of different cardiac structures.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n We used tissue\u2010specific knockout mouse models of\n Robo1<\/jats:italic>\n \/\n Robo2<\/jats:italic>\n ,\n Robo4<\/jats:italic>\n ,\n Slit2<\/jats:italic>\n and\n Slit3<\/jats:italic>\n and scored cardiac developmental defects in perinatal mice. Knockout of\n Robo2<\/jats:italic>\n in either the whole heart, endocardium and its derivatives, or the neural crest in ubiquitous\n Robo1<\/jats:italic>\n knockout background resulted in ventricular septal defects. Neural crest\u2010specific removal of\n Robo2<\/jats:italic>\n in\n Robo1<\/jats:italic>\n knockouts showed fully penetrant bicuspid aortic valves (BAV). Endocardial knock\u2010out of either\n Slit2<\/jats:italic>\n or\n Robo4<\/jats:italic>\n caused low penetrant BAV. In contrast, endocardial knockout of\n Slit3<\/jats:italic>\n using a newly generated line resulted in fully penetrant BAV, while removal from smooth muscle cells also resulted in BAV. Caval vein and diaphragm defects observed in ubiquitous\n Slit3<\/jats:italic>\n mutants were recapitulated in the tissue\u2010specific knockouts.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our data will help understand defects observed in patients with variants in\n ROBO1<\/jats:italic>\n and\n ROBO4<\/jats:italic>\n . The results strongly indicate interaction between endocardial\n Slit3<\/jats:italic>\n and neural crest\n Robo2<\/jats:italic>\n in the development of BAV, highlighting the need for further studies of this connection.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.121.023348","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T09:11:54Z","timestamp":1648458714000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Tissue\u2010Specific Roles for the Slit\u2013Robo Pathway During Heart, Caval Vein, and Diaphragm Development"],"prefix":"10.1161","volume":"11","author":[{"given":"Juanjuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics Burdon Sanderson Cardiac Science Centre University of Oxford United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5814-7166","authenticated-orcid":false,"given":"Susann","family":"Bruche","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics Burdon Sanderson Cardiac Science Centre University of Oxford United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7829-7823","authenticated-orcid":false,"given":"Helen G.","family":"Potts","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics Burdon Sanderson Cardiac Science Centre University of Oxford United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3623-600X","authenticated-orcid":false,"given":"Benjamin","family":"Davies","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine Wellcome Centre for Human GeneticsUniversity of Oxford United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6624-3038","authenticated-orcid":false,"given":"Mathilda T. M.","family":"Mommersteeg","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics Burdon Sanderson Cardiac Science Centre University of Oxford United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-104611"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0265-y"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.277426"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv040"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.11.018"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.009"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3849"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhr330"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10022"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(07)00562-3"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.193.6.741"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1666"},{"key":"e_1_3_1_14_2","first-page":"1","article-title":"New concepts in the development and malformation of the arterial valves","volume":"7","author":"Henderson DJ","year":"2020","unstructured":"Henderson DJ, Eley L, Chaudhry B. New concepts in the development and malformation of the arterial valves. J Cardiovasc Dev Dis. 2020;7:1\u201327. doi: 10.3390\/jcdd7040038","journal-title":"J Cardiovasc Dev Dis"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.121.023348","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T11:33:52Z","timestamp":1715600032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.121.023348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,5]]},"references-count":13,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,4,5]]}},"alternative-id":["10.1161\/JAHA.121.023348"],"URL":"https:\/\/doi.org\/10.1161\/jaha.121.023348","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,5]]},"assertion":[{"value":"2021-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e023348"}}