{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:46:52Z","timestamp":1788281212354,"version":"build-2803163510"},"reference-count":38,"publisher":"American Physiological Society","issue":"6","funder":[{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD090309"],"award-info":[{"award-number":["HD090309"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2021,6,1]]},"abstract":"<jats:p> The TGF-\u03b2 signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-\u03b2 signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-\u03b2 signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-\u03b2 signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-\u03b2 receptor 2 gene ( Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1\/2 may mediate these mesenchymal effects of TGF-\u03b2 signaling through the GSK3\u03b2-\u03b2-catenin-Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-\u03b2 signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-\u03b2 signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions. <\/jats:p>","DOI":"10.1152\/ajplung.00299.2020","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T19:23:05Z","timestamp":1619032985000},"page":"L1158-L1168","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Abrogation of mesenchyme-specific TGF-\u03b2 signaling results in lung malformation with prenatal pulmonary cysts in mice"],"prefix":"10.1152","volume":"320","author":[{"given":"Qing","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Surgery, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California"},{"name":"Department of Allergy, Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health, Beijing, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1083-2703","authenticated-orcid":true,"given":"Matthew E.","family":"Thornton","sequence":"additional","affiliation":[{"name":"Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan H.","family":"Grubbs","sequence":"additional","affiliation":[{"name":"Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kolb","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlin","family":"Lou","sequence":"additional","affiliation":[{"name":"Institute of Occupational Diseases, Hangzhou Medical College (Zhejiang Academy of Medical Science), Hangzhou, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6499-2473","authenticated-orcid":true,"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Children\u2019s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.12.010"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s0070-2153(10)90003-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2015.01.011"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000159570.01327.ED"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00432-X"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature02006"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00165407"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-11-111"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10046"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.14806\/ej.17.1.200"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-98141-3"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-015-0153-1"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0012-1606(03)00315-4"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070286"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00298.2004"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/stem.68"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1996.0259"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70291"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.120398"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41777-y"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20917"},{"key":"B27","first-page":"22","volume":"6","author":"Di PF","year":"2012","journal-title":"J Prenat Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1053\/j.sempedsurg.2015.01.013"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1080\/15513810902984095"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1053\/j.sempedsurg.2010.03.003"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.08.012"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.02.001"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700376"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.3.2099"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9440(10)61252-7"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/463740"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.220413597"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7150\/thno.14334"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.06.009"}],"container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajplung.00299.2020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T08:43:38Z","timestamp":1624437818000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajplung.00299.2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6,1]]}},"alternative-id":["10.1152\/ajplung.00299.2020"],"URL":"https:\/\/doi.org\/10.1152\/ajplung.00299.2020","relation":{},"ISSN":["1040-0605","1522-1504"],"issn-type":[{"value":"1040-0605","type":"print"},{"value":"1522-1504","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,1]]},"assertion":[{"value":"2020-06-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}