{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:35:59Z","timestamp":1791286559612,"version":"4.1.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T00:00:00Z","timestamp":1470096000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T00:00:00Z","timestamp":1470096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Branching morphogenesis is a complex biological process common to the development of most epithelial organs. Here we demonstrate that NF2, LATS1\/2 and YAP play a critical role in branching morphogenesis in the mouse kidney. Removal of <jats:italic>Nf2<\/jats:italic> or <jats:italic>Lats1<\/jats:italic>\/<jats:italic>2<\/jats:italic> from the ureteric bud (UB) lineage causes loss of branching morphogenesis that is rescued by loss of one copy of <jats:italic>Yap<\/jats:italic> and <jats:italic>Taz<\/jats:italic>, and phenocopied by YAP overexpression. Mosaic analysis demonstrates that cells with high YAP expression have reduced contribution to UB tips, similar to <jats:italic>Ret<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> cells, and that YAP suppresses RET signalling and tip identity. Conversely, <jats:italic>Yap<\/jats:italic>\/<jats:italic>Taz<\/jats:italic> UB-deletion leads to cyst-like branching and expansion of UB tip markers, suggesting a shift towards tip cell identity. Based on these data we propose that NF2 and the Hippo pathway locally repress YAP\/TAZ activity in the UB to promote subsequent splitting of the tip to allow branching morphogenesis.<\/jats:p>","DOI":"10.1038\/ncomms12309","type":"journal-article","created":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T10:04:02Z","timestamp":1470132242000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["A critical role for NF2 and the Hippo pathway in branching morphogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"Antoine","family":"Reginensi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Enderle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Gregorieff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy L.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Wrana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"McNeill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,2]]},"reference":[{"key":"BFncomms12309_CR1","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/j.devcel.2010.04.008","volume":"18","author":"F Costantini","year":"2010","unstructured":"Costantini, F. & Kopan, R. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev. Cell 18, 698\u2013712 (2010).","journal-title":"Dev. Cell"},{"key":"BFncomms12309_CR2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.devcel.2014.02.017","volume":"29","author":"KM Short","year":"2014","unstructured":"Short, K. M. et al. Global quantification of tissue dynamics in the developing mouse kidney. Dev. Cell 29, 188\u2013202 (2014).","journal-title":"Dev. Cell"},{"key":"BFncomms12309_CR3","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1002\/wdev.52","volume":"1","author":"F Costantini","year":"2012","unstructured":"Costantini, F. Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system. Wiley Interdiscip. Rev. Dev. Biol. 1, 693\u2013713 (2012).","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"BFncomms12309_CR4","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.devcel.2004.11.008","volume":"8","author":"R Shakya","year":"2005","unstructured":"Shakya, R., Watanabe, T. & Costantini, F. The role of GDNF\/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev. Cell 8, 65\u201374 (2005).","journal-title":"Dev. Cell"},{"key":"BFncomms12309_CR5","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/382076a0","volume":"382","author":"MW Moore","year":"1996","unstructured":"Moore, M. W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76\u201379 (1996).","journal-title":"Nature"},{"key":"BFncomms12309_CR6","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1038\/367380a0","volume":"367","author":"A Schuchardt","year":"1994","unstructured":"Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F. & Pachnis, V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380\u2013383 (1994).","journal-title":"Nature"},{"key":"BFncomms12309_CR7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0896-6273(00)80514-0","volume":"21","author":"G Cacalano","year":"1998","unstructured":"Cacalano, G. et al. GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21, 53\u201362 (1998).","journal-title":"Neuron"},{"key":"BFncomms12309_CR8","doi-asserted-by":"publisher","first-page":"2743","DOI":"10.1016\/j.febslet.2014.04.001","volume":"588","author":"J Cooper","year":"2014","unstructured":"Cooper, J. & Giancotti, F. G. Molecular insights into NF2\/Merlin tumor suppressor function. FEBS Lett. 588, 2743\u20132752 (2014).","journal-title":"FEBS Lett."},{"key":"BFncomms12309_CR9","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrclinonc.2013.144","volume":"10","author":"AL Lin","year":"2013","unstructured":"Lin, A. L. & Gutmann, D. H. Advances in the treatment of neurofibromatosis-associated tumours. Nat. Rev. Clin. Oncol. 10, 616\u2013624 (2013).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"BFncomms12309_CR10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.18632\/oncotarget.1557","volume":"5","author":"RD Schroeder","year":"2014","unstructured":"Schroeder, R. D., Angelo, L. S. & Kurzrock, R. NF2\/merlin in hereditary neurofibromatosis 2 versus cancer: biologic mechanisms and clinical associations. Oncotarget 5, 67\u201377 (2014).","journal-title":"Oncotarget"},{"key":"BFncomms12309_CR11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/dvdy.22723","volume":"241","author":"BK Staley","year":"2012","unstructured":"Staley, B. K. & Irvine, K. D. Hippo signaling in Drosophila: recent advances and insights. Dev. Dyn. 241, 3\u201315 (2012).","journal-title":"Dev. Dyn."},{"key":"BFncomms12309_CR12","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.ceb.2008.10.001","volume":"20","author":"B Zhao","year":"2008","unstructured":"Zhao, B., Lei, Q. Y. & Guan, K. L. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr. Opin. Cell Biol. 20, 638\u2013646 (2008).","journal-title":"Curr. Opin. Cell Biol."},{"key":"BFncomms12309_CR13","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1242\/dev.045500","volume":"138","author":"G Halder","year":"2011","unstructured":"Halder, G. & Johnson, R. L. Hippo signaling: growth control and beyond. Development 138, 9\u201322 (2011).","journal-title":"Development"},{"key":"BFncomms12309_CR14","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.devcel.2010.09.011","volume":"19","author":"D Pan","year":"2010","unstructured":"Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491\u2013505 (2010).","journal-title":"Dev. Cell"},{"key":"BFncomms12309_CR15","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nrc2070","volume":"7","author":"K Harvey","year":"2007","unstructured":"Harvey, K. & Tapon, N. The Salvador-Warts-Hippo pathway \u2013 an emerging tumour-suppressor network. Nat. Rev. Cancer 7, 182\u2013191 (2007).","journal-title":"Nat. Rev. Cancer"},{"key":"BFncomms12309_CR16","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1016\/j.cell.2013.08.025","volume":"154","author":"F Yin","year":"2013","unstructured":"Yin, F. et al. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin\/NF2. Cell 154, 1342\u20131355 (2013).","journal-title":"Cell"},{"key":"BFncomms12309_CR17","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","volume":"163","author":"FX Yu","year":"2015","unstructured":"Yu, F. X., Zhao, B. & Guan, K. L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811\u2013828 (2015).","journal-title":"Cell"},{"key":"BFncomms12309_CR18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nature10137","volume":"474","author":"S Dupont","year":"2011","unstructured":"Dupont, S. et al. Role of YAP\/TAZ in mechanotransduction. Nature 474, 179\u2013183 (2011).","journal-title":"Nature"},{"key":"BFncomms12309_CR19","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.ydbio.2004.09.002","volume":"276","author":"H Zhao","year":"2004","unstructured":"Zhao, H. et al. Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev. Biol. 276, 403\u2013415 (2004).","journal-title":"Dev. Biol."},{"key":"BFncomms12309_CR20","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1038\/ng.476","volume":"41","author":"BC Lu","year":"2009","unstructured":"Lu, B. C. et al. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat. Genet. 41, 1295\u20131302 (2009).","journal-title":"Nat. Genet."},{"key":"BFncomms12309_CR21","doi-asserted-by":"publisher","first-page":"e1004193","DOI":"10.1371\/journal.pgen.1004193","volume":"10","author":"A Ihermann-Hella","year":"2014","unstructured":"Ihermann-Hella, A. et al. Mitogen-activated protein kinase (MAPK) pathway regulates branching by remodeling epithelial cell adhesion. PLoS Genet. 10, e1004193 (2014).","journal-title":"PLoS Genet."},{"key":"BFncomms12309_CR22","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.devcel.2010.10.008","volume":"19","author":"AB Gladden","year":"2010","unstructured":"Gladden, A. B., Hebert, A. M., Schneeberger, E. E. & McClatchey, A. I. The NF2 tumor suppressor, Merlin, regulates epidermal development through the establishment of a junctional polarity complex. Dev. Cell 19, 727\u2013739 (2010).","journal-title":"Dev. Cell"},{"key":"BFncomms12309_CR23","doi-asserted-by":"publisher","first-page":"3323","DOI":"10.1242\/dev.096537","volume":"140","author":"A Lavado","year":"2013","unstructured":"Lavado, A. et al. Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap\/Taz transcriptional coactivators. Development 140, 3323\u20133334 (2013).","journal-title":"Development"},{"key":"BFncomms12309_CR24","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1242\/dev.051656","volume":"137","author":"S Kuure","year":"2010","unstructured":"Kuure, S., Chi, X., Lu, B. & Costantini, F. The transcription factors Etv4 and Etv5 mediate formation of the ureteric bud tip domain during kidney development. Development 137, 1975\u20131979 (2010).","journal-title":"Development"},{"key":"BFncomms12309_CR25","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.devcel.2013.09.001","volume":"27","author":"A Packard","year":"2013","unstructured":"Packard, A. et al. Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud. Dev. Cell 27, 319\u2013330 (2013).","journal-title":"Dev. Cell"},{"key":"BFncomms12309_CR26","doi-asserted-by":"publisher","first-page":"2696","DOI":"10.1242\/dev.122044","volume":"142","author":"A Reginensi","year":"2015","unstructured":"Reginensi, A. et al. Yap and Taz are required for Ret-dependent urinary tract morphogenesis. Development 142, 2696\u20132703 (2015).","journal-title":"Development"},{"key":"BFncomms12309_CR27","doi-asserted-by":"publisher","first-page":"e1003380","DOI":"10.1371\/journal.pgen.1003380","volume":"9","author":"A Reginensi","year":"2013","unstructured":"Reginensi, A. et al. Yap- and Cdc42-dependent nephrogenesis and morphogenesis during mouse kidney development. PLoS Genet. 9, e1003380 (2013).","journal-title":"PLoS Genet."},{"key":"BFncomms12309_CR28","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1126\/science.1199010","volume":"332","author":"T Heallen","year":"2011","unstructured":"Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458\u2013461 (2011).","journal-title":"Science"},{"key":"BFncomms12309_CR29","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1101\/gad.14.13.1617","volume":"14","author":"M Giovannini","year":"2000","unstructured":"Giovannini, M. et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 14, 1617\u20131630 (2000).","journal-title":"Genes Dev."},{"key":"BFncomms12309_CR30","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/nature15382","volume":"526","author":"A Gregorieff","year":"2015","unstructured":"Gregorieff, A., Liu, Y., Inanlou, M. R., Khomchuk, Y. & Wrana, J. L. Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 526, 715\u2013718 (2015).","journal-title":"Nature"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms12309.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12309","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12309.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T10:38:10Z","timestamp":1672828690000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms12309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,2]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,25]]}},"alternative-id":["BFncomms12309"],"URL":"https:\/\/doi.org\/10.1038\/ncomms12309","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,2]]},"assertion":[{"value":"4 December 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12309"}}