{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:19:09Z","timestamp":1789510749343,"version":"build-2803163510"},"reference-count":65,"publisher":"American Society for Clinical Investigation","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,19]]},"abstract":"<jats:p>\n                    Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that\n                    <jats:italic>Robo2<\/jats:italic>\n                    deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKC\u03c2, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53\/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKC\u03c2, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of\n                    <jats:italic>Robo2<\/jats:italic>\n                    and\n                    <jats:italic>p53<\/jats:italic>\n                    rescued all the epithelial defects in kidneys compared with those in\n                    <jats:italic>Robo2<\/jats:italic>\n                    -knockout kidneys. Taken together, the present results demonstrate that\n                    <jats:italic>Robo2<\/jats:italic>\n                    deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.127602","type":"journal-article","created":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T11:00:55Z","timestamp":1568804455000},"source":"Crossref","is-referenced-by-count":7,"title":["Disruption of Robo2-Baiap2 integrated signaling drives cystic disease"],"prefix":"10.1172","volume":"4","author":[{"given":"Qinggang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyuan","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GuangRui","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewud","family":"Agborbesong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongyu","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyuan","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuansheng","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangmei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Chinese PLA General Hospital, Medical School of Chinese PLA, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,9,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22708"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/GCO.0000000000000348"},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.1038\/srep17699","article-title":"Mouse Crumbs3 sustains epithelial tissue morphogenesis in vivo","volume":"5","author":"Charrier","year":"2015","journal-title":"Sci Rep"},{"issue":"3","key":"B4","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.bbamem.2007.09.001","article-title":"Tight junction and polarity interaction in the transporting epithelial phenotype","volume":"1778","author":"Cereijido","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011111121"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90330-T"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90249-8"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-015-1570-5"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(04)00108-X"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.508"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1086\/512735"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.100"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3392"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006070739"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1159\/000020498"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2012.03.034"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.06.021"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016070748"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.09.015"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.034"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.12.071"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa013413"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.06.002"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2781"},{"issue":"pt 19","key":"B25","first-page":"4543","article-title":"LIN7 regulates the filopodium- and neurite-promoting activity of IRSp53","volume":"125","author":"Crespi","year":"2012","journal-title":"J Cell Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01259-08"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2008.00854.x"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009070698"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.05.007"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.019"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.1218351"},{"issue":"pt 20","key":"B32","first-page":"4396","article-title":"CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway","volume":"127","author":"Ruan","year":"2014","journal-title":"J Cell Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1095"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.07.007"},{"issue":"14","key":"B35","first-page":"1017","article-title":"Posttranslational modification of MDM2","volume":"1","author":"Meek","year":"2003","journal-title":"Mol Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.68"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.043"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010010061"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.188185"},{"key":"B40","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms3658","article-title":"Polycystin-1 binds Par3\/aPKC and controls convergent extension during renal tubular morphogenesis","volume":"4","author":"Castelli","year":"2013","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102617108"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1502"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80416-X"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.181181198"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1101-973"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.7.836"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.03.017"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64401"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2003.10.008"},{"key":"B50","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms1678","article-title":"CPEB-mediated ZO-1 mRNA localization is required for epithelial tight-junction assembly and cell polarity","volume":"3","author":"Nagaoka","year":"2012","journal-title":"Nat Commun"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201490594"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s11418-014-0817-0"},{"issue":"2","key":"B53","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.125490","article-title":"Epithelial innate immunity mediates tubular cell senescence after kidney injury","volume":"4","author":"Jin","year":"2019","journal-title":"JCI Insight"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.03.020"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0262"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1385"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3472"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3863"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3849"},{"issue":"19","key":"B60","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.86934","article-title":"SLIT2\/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion","volume":"1","author":"Fan","year":"2016","journal-title":"JCI Insight"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-913-0_14"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2245"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/nature12416"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008040435"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3092"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/127602\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:24:32Z","timestamp":1779193472000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/127602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,19]]},"references-count":65,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9,19]]},"published-print":{"date-parts":[[2019,9,19]]}},"alternative-id":["10.1172\/jci.insight.127602"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.127602","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,19]]},"article-number":"e127602"}}