{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:49:04Z","timestamp":1790106544749,"version":"4.0.1"},"reference-count":96,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P01HD093363"],"award-info":[{"award-number":["P01HD093363"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL092153"],"award-info":[{"award-number":["R01HL092153"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL124836"],"award-info":[{"award-number":["R01HL124836"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM007183"],"award-info":[{"award-number":["T32GM007183"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["T32HL007381"],"award-info":[{"award-number":["T32HL007381"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2021,9,23]]},"abstract":"<jats:p>\n                    The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using\n                    <jats:italic>Xenopus<\/jats:italic>\n                    and mouse embryos, we establish molecular links between Tbx5 and retinoic acid (RA) signaling in the mesoderm and between RA signaling and sonic hedgehog expression in the endoderm to unveil a conserved RA-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary (CP) development. We demonstrate that Tbx5 directly maintains expression of\n                    <jats:italic>aldh1a2,<\/jats:italic>\n                    the RA-synthesizing enzyme, in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module to restrict FGF activity to the anterior. We find that Tbx5\/Aldh1a2-dependent RA signaling directly activates\n                    <jats:italic>shh<\/jats:italic>\n                    transcription in the adjacent foregut endoderm through a conserved MACS1 enhancer. Hedgehog signaling coordinates with Tbx5 in the mesoderm to activate expression of\n                    <jats:italic>wnt2\/2b,<\/jats:italic>\n                    which induces pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing CP evolution and birth defects.\n                  <\/jats:p>","DOI":"10.7554\/elife.69288","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T08:59:08Z","timestamp":1634115548000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.69288","source":"Crossref","is-referenced-by-count":28,"title":["Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3953-6016","authenticated-orcid":true,"given":"Scott A","family":"Rankin","sequence":"first","affiliation":[{"name":"Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D","family":"Steimle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Pathology, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Human Genetics, University of Chicago","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinan H","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Pathology, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Human Genetics, University of Chicago","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel B","family":"Rydeen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Pathology, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Human Genetics, University of Chicago","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunal","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praneet","family":"Chaturvedi","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohta","family":"Ikegami","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Chicago","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-9515","authenticated-orcid":true,"given":"Michael J","family":"Herriges","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Chicago","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-4963","authenticated-orcid":true,"given":"Ivan P","family":"Moskowitz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Pathology, University of Chicago","place":["Chicago, United States"]},{"name":"Department of Human Genetics, University of Chicago","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3217-3590","authenticated-orcid":true,"given":"Aaron M","family":"Zorn","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Perinatal Institute, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, United States"]},{"name":"University of Cincinnati, College of Medicine, Department of Pediatrics","place":["Chicago, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"3219","DOI":"10.1093\/hmg\/ddl399","article-title":"Dissection of Tbx1 and Fgf interactions in mouse models of 22q11DS suggests functional redundancy","volume":"15","author":"Aggarwal","year":"2006","journal-title":"Human Molecular 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