{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:15:40Z","timestamp":1792631740987,"version":"4.5.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T00:00:00Z","timestamp":1553731200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T00:00:00Z","timestamp":1553731200000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cell-line derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3\u2032 untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing\n                    <jats:italic>Gdnf<\/jats:italic>\n                    . We demonstrate that increased\n                    <jats:italic>Gdnf<\/jats:italic>\n                    leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand\u00a0collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF\u2019s effects on progenitors. Moreover,\n                    <jats:italic>Gdnf<\/jats:italic>\n                    \u200a\u200a\u200a\n                    <jats:sup>hyper<\/jats:sup>\n                    mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3\u2032UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and\/or congenital infertility cases in humans\u00a0and pave way to future studies.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-40457-1","type":"journal-article","created":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T07:03:05Z","timestamp":1553756585000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Development of the urogenital system is regulated via the 3\u2032UTR of GDNF"],"prefix":"10.1038","volume":"9","author":[{"given":"Hao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madis","family":"Jakobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"Ola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujuan","family":"Gui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anmol","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Sipil\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannu","family":"Sariola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9076-0622","authenticated-orcid":false,"given":"Satu","family":"Kuure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0271-3157","authenticated-orcid":false,"given":"Jaan-Olle","family":"Andressoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,28]]},"reference":[{"key":"40457_CR1","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1038\/nrneph.2015.140","volume":"11","author":"N Nicolaou","year":"2015","unstructured":"Nicolaou, N., Renkema, K. Y., Bongers, E. M., Giles, R. H. & Knoers, N. V. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol 11, 720\u2013731, https:\/\/doi.org\/10.1038\/nrneph.2015.140 (2015).","journal-title":"Nat Rev Nephrol"},{"key":"40457_CR2","doi-asserted-by":"publisher","unstructured":"Heidet, L. et al. Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol, https:\/\/doi.org\/10.1681\/ASN.2017010043 (2017).","DOI":"10.1681\/ASN.2017010043"},{"key":"40457_CR3","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1242\/dev.117903","volume":"142","author":"KM Georgas","year":"2015","unstructured":"Georgas, K. M. et al. An illustrated anatomical ontology of the developing mouse lower urogenital tract. Development 142, 1893\u20131908, https:\/\/doi.org\/10.1242\/dev.117903 (2015).","journal-title":"Development"},{"key":"40457_CR4","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1159\/000096644","volume":"67","author":"SE Hannema","year":"2007","unstructured":"Hannema, S. E. & Hughes, I. A. Regulation of Wolffian duct development. Horm Res 67, 142\u2013151, https:\/\/doi.org\/10.1159\/000096644 (2007).","journal-title":"Horm Res"},{"key":"40457_CR5","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.diff.2011.04.008","volume":"82","author":"T Kurita","year":"2011","unstructured":"Kurita, T. Normal and abnormal epithelial differentiation in the female reproductive tract. Differentiation 82, 117\u2013126, https:\/\/doi.org\/10.1016\/j.diff.2011.04.008 (2011).","journal-title":"Differentiation"},{"key":"40457_CR6","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.jpag.2005.06.008","volume":"18","author":"R Sakalkale","year":"2005","unstructured":"Sakalkale, R. & Samarakkody, U. Familial occurrence of imperforate hymen. J Pediatr Adolesc Gynecol 18, 427\u2013429, https:\/\/doi.org\/10.1016\/j.jpag.2005.06.008 (2005).","journal-title":"J Pediatr Adolesc Gynecol"},{"key":"40457_CR7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jpag.2011.08.003","volume":"25","author":"N Kimberley","year":"2012","unstructured":"Kimberley, N., Hutson, J. M., Southwell, B. R. & Grover, S. R. Vaginal agenesis, the hymen, and associated anomalies. J Pediatr Adolesc Gynecol 25, 54\u201358, https:\/\/doi.org\/10.1016\/j.jpag.2011.08.003 (2012).","journal-title":"J Pediatr Adolesc Gynecol"},{"key":"40457_CR8","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 interdisciplinary reviews. Developmental biology 1, 693\u2013713, https:\/\/doi.org\/10.1002\/wdev.52 (2012).","journal-title":"Wiley interdisciplinary reviews. Developmental biology"},{"key":"40457_CR9","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1111\/j.1399-0004.2009.01175.x","volume":"75","author":"N Uetani","year":"2009","unstructured":"Uetani, N. & Bouchard, M. Plumbing in the embryo: developmental defects of the urinary tracts. Clin Genet 75, 307\u2013317 (2009).","journal-title":"Clin Genet"},{"key":"40457_CR10","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/S0022-5347(17)67007-1","volume":"114","author":"GG Mackie","year":"1975","unstructured":"Mackie, G. G. & Stephens, F. D. Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol 114, 274\u2013280 (1975).","journal-title":"J Urol"},{"key":"40457_CR11","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1159\/000364935","volume":"8","author":"RD Mullen","year":"2014","unstructured":"Mullen, R. D. & Behringer, R. R. Molecular genetics of Mullerian duct formation, regression and differentiation. Sex Dev 8, 281\u2013296, https:\/\/doi.org\/10.1159\/000364935 (2014).","journal-title":"Sex Dev"},{"key":"40457_CR12","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/ng952","volume":"32","author":"E Batourina","year":"2002","unstructured":"Batourina, E. et al. Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet 32, 109\u2013115 (2002).","journal-title":"Nat Genet"},{"key":"40457_CR13","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1006\/exnr.1999.7127","volume":"158","author":"JP Golden","year":"1999","unstructured":"Golden, J. P., DeMaro, J. A., Osborne, P. A., Milbrandt, J. & Johnson, E. M. Jr. Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse. Exp Neurol 158, 504\u2013528 (1999).","journal-title":"Exp Neurol"},{"key":"40457_CR14","doi-asserted-by":"publisher","first-page":"3420","DOI":"10.1242\/dev.113928","volume":"141","author":"AC Weiss","year":"2014","unstructured":"Weiss, A. C. et al. Nephric duct insertion requires EphA4\/EphA7 signaling from the pericloacal mesenchyme. Development 141, 3420\u20133430, https:\/\/doi.org\/10.1242\/dev.113928 (2014).","journal-title":"Development"},{"key":"40457_CR15","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.semcdb.2014.09.001","volume":"36","author":"K Stewart","year":"2014","unstructured":"Stewart, K. & Bouchard, M. Coordinated cell behaviours in early urogenital system morphogenesis. Semin Cell Dev Biol 36, 13\u201320, https:\/\/doi.org\/10.1016\/j.semcdb.2014.09.001 (2014).","journal-title":"Semin Cell Dev Biol"},{"key":"40457_CR16","doi-asserted-by":"publisher","first-page":"252","DOI":"10.4161\/org.6.4.12680","volume":"6","author":"F Costantini","year":"2010","unstructured":"Costantini, F. GDNF\/Ret signaling and renal branching morphogenesis: From mesenchymal signals to epithelial cell behaviors. Organogenesis 6, 252\u2013262, https:\/\/doi.org\/10.4161\/org.6.4.12680 (2010).","journal-title":"Organogenesis"},{"key":"40457_CR17","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1242\/dev.056838","volume":"138","author":"I Chia","year":"2011","unstructured":"Chia, I. et al. Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice. Development 138, 2089\u20132097, https:\/\/doi.org\/10.1242\/dev.056838 (2011).","journal-title":"Development"},{"key":"40457_CR18","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1242\/dev.078667","volume":"139","author":"M Hoshi","year":"2012","unstructured":"Hoshi, M., Batourina, E., Mendelsohn, C. & Jain, S. Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice. Development 139, 2405\u20132415, https:\/\/doi.org\/10.1242\/dev.078667 (2012).","journal-title":"Development"},{"key":"40457_CR19","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nrneph.2016.157","volume":"12","author":"KM Short","year":"2016","unstructured":"Short, K. M. & Smyth, I. M. The contribution of branching morphogenesis to kidney development and disease. Nat Rev Nephrol 12, 754\u2013767, https:\/\/doi.org\/10.1038\/nrneph.2016.157 (2016).","journal-title":"Nat Rev Nephrol"},{"key":"40457_CR20","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":"40457_CR21","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/382070a0","volume":"382","author":"MP Sanchez","year":"1996","unstructured":"Sanchez, M. P. et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70\u201373 (1996).","journal-title":"Nature"},{"key":"40457_CR22","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/382073a0","volume":"382","author":"JG Pichel","year":"1996","unstructured":"Pichel, J. G. et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73\u201376 (1996).","journal-title":"Nature"},{"key":"40457_CR23","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ydbio.2005.04.008","volume":"283","author":"R Shakya","year":"2005","unstructured":"Shakya, R. et al. The role of GDNF in patterning the excretory system. Dev Biol 283, 70\u201384 (2005).","journal-title":"Dev Biol"},{"key":"40457_CR24","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/S1534-5807(04)00108-X","volume":"6","author":"U Grieshammer","year":"2004","unstructured":"Grieshammer, U. et al. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev Cell 6, 709\u2013717 (2004).","journal-title":"Dev Cell"},{"key":"40457_CR25","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.devcel.2004.12.004","volume":"8","author":"MA Basson","year":"2005","unstructured":"Basson, M. A. et al. Sprouty1 is a critical regulator of GDNF\/RET-mediated kidney induction. Dev Cell 8, 229\u2013239 (2005).","journal-title":"Dev Cell"},{"key":"40457_CR26","doi-asserted-by":"publisher","first-page":"e1005710","DOI":"10.1371\/journal.pgen.1005710","volume":"11","author":"A Kumar","year":"2015","unstructured":"Kumar, A. et al. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. PLoS Genet 11, e1005710, https:\/\/doi.org\/10.1371\/journal.pgen.1005710 (2015).","journal-title":"PLoS Genet"},{"key":"40457_CR27","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, https:\/\/doi.org\/10.1016\/j.devcel.2013.09.001 (2013).","journal-title":"Dev Cell"},{"key":"40457_CR28","first-page":"924","volume":"119","author":"N Uetani","year":"2009","unstructured":"Uetani, N. et al. Maturation of ureter-bladder connection in mice is controlled by LAR family receptor protein tyrosine phosphatases. J Clin Invest 119, 924\u2013935 (2009).","journal-title":"J Clin Invest"},{"key":"40457_CR29","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1038\/ng1645","volume":"37","author":"E Batourina","year":"2005","unstructured":"Batourina, E. et al. Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder. Nat Genet 37, 1082\u20131089 (2005).","journal-title":"Nat Genet"},{"key":"40457_CR30","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":"40457_CR31","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ydbio.2004.03.025","volume":"271","author":"T Watanabe","year":"2004","unstructured":"Watanabe, T. & Costantini, F. Real-time analysis of ureteric bud branching morphogenesis in vitro. Dev Biol 271, 98\u2013108 (2004).","journal-title":"Dev Biol"},{"key":"40457_CR32","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":"40457_CR33","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1111\/j.0021-8782.2004.00285.x","volume":"204","author":"L Michael","year":"2004","unstructured":"Michael, L. & Davies, J. A. Pattern and regulation of cell proliferation during murine ureteric bud development. J Anat 204, 241\u2013255 (2004).","journal-title":"J Anat"},{"key":"40457_CR34","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1242\/dev.022145","volume":"135","author":"D Sweeney","year":"2008","unstructured":"Sweeney, D., Lindstrom, N. & Davies, J. A. Developmental plasticity and regenerative capacity in the renal ureteric bud\/collecting duct system. Development 135, 2505\u20132510 (2008).","journal-title":"Development"},{"key":"40457_CR35","doi-asserted-by":"publisher","first-page":"e1002382","DOI":"10.1371\/journal.pbio.1002382","volume":"14","author":"P Riccio","year":"2016","unstructured":"Riccio, P., Cebrian, C., Zong, H., Hippenmeyer, S. & Costantini, F. Ret and Etv4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis. PLoS Biol 14, e1002382, https:\/\/doi.org\/10.1371\/journal.pbio.1002382 (2016).","journal-title":"PLoS Biol"},{"key":"40457_CR36","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, https:\/\/doi.org\/10.1242\/dev.051656 (2010).","journal-title":"Development"},{"key":"40457_CR37","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/nn.3941","volume":"18","author":"J Kopra","year":"2015","unstructured":"Kopra, J. et al. GDNF is not required for catecholaminergic neuron survival in vivo. Nature neuroscience 18, 319\u2013322, https:\/\/doi.org\/10.1038\/nn.3941 (2015).","journal-title":"Nature neuroscience"},{"key":"40457_CR38","doi-asserted-by":"publisher","unstructured":"Kurtzeborn, K., Cebrian, C. & Kuure, S. Regulation of renal differentiation by trophic factors. Frontiers in Physiology, https:\/\/doi.org\/10.3389\/fphys.2018.01588 (2018).","DOI":"10.3389\/fphys.2018.01588"},{"key":"40457_CR39","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1242\/dev.128.21.4329","volume":"128","author":"CE Fisher","year":"2001","unstructured":"Fisher, C. E., Michael, L., Barnett, M. W. & Davies, J. A. Erk MAP kinase regulates branching morphogenesis in the developing mouse kidney. Development 128, 4329\u20134338 (2001).","journal-title":"Development"},{"key":"40457_CR40","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1006\/dbio.2001.0557","volume":"243","author":"MJ Tang","year":"2002","unstructured":"Tang, M. J., Cai, Y., Tsai, S. J., Wang, Y. K. & Dressler, G. R. Ureteric bud outgrowth in response to RET activation is mediated by phosphatidylinositol 3-kinase. Dev Biol 243, 128\u2013136 (2002).","journal-title":"Dev Biol"},{"key":"40457_CR41","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, https:\/\/doi.org\/10.1371\/journal.pgen.1004193 (2014).","journal-title":"PLoS Genet"},{"key":"40457_CR42","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1046\/j.1523-1755.2001.00767.x","volume":"60","author":"LA Cullen-McEwen","year":"2001","unstructured":"Cullen-McEwen, L. A., Drago, J. & Bertram, J. F. Nephron endowment in glial cell line-derived neurotrophic factor (GDNF) heterozygous mice. Kidney Int 60, 31\u201336 (2001).","journal-title":"Kidney Int"},{"key":"40457_CR43","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1126\/science.287.5457.1489","volume":"287","author":"X Meng","year":"2000","unstructured":"Meng, X. et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489\u20131493 (2000).","journal-title":"Science"},{"key":"40457_CR44","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, https:\/\/doi.org\/10.1016\/j.devcel.2010.04.008 (2010).","journal-title":"Dev Cell"},{"key":"40457_CR45","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1210\/me.2014-1312","volume":"29","author":"HJ Park","year":"2015","unstructured":"Park, H. J. & Bolton, E. C. Glial cell line-derived neurotrophic factor induces cell proliferation in the mouse urogenital sinus. Mol Endocrinol 29, 289\u2013306, https:\/\/doi.org\/10.1210\/me.2014-1312 (2015).","journal-title":"Mol Endocrinol"},{"key":"40457_CR46","doi-asserted-by":"publisher","first-page":"7909","DOI":"10.1038\/sj.onc.1210591","volume":"26","author":"P Runeberg-Roos","year":"2007","unstructured":"Runeberg-Roos, P., Virtanen, H. & Saarma, M. RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface. Oncogene 26, 7909\u20137915, https:\/\/doi.org\/10.1038\/sj.onc.1210591 (2007).","journal-title":"Oncogene"},{"key":"40457_CR47","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1093\/emboj\/19.4.612","volume":"19","author":"CL Smith-Hicks","year":"2000","unstructured":"Smith-Hicks, C. L., Sizer, K. C., Powers, J. F., Tischler, A. S. & Costantini, F. C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. Embo J 19, 612\u2013622 (2000).","journal-title":"Embo J"},{"key":"40457_CR48","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1507\/endocrj.EJ13-0335","volume":"61","author":"Y Hibi","year":"2014","unstructured":"Hibi, Y. et al. A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis. Endocr J 61, 19\u201323 (2014).","journal-title":"Endocr J"},{"key":"40457_CR49","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1056\/NEJM200004203421615","volume":"342","author":"F Lore","year":"2000","unstructured":"Lore, F., Di Cairano, G. & Talidis, F. Unilateral renal agenesis in a family with medullary thyroid carcinoma. N Engl J Med 342, 1218\u20131219, https:\/\/doi.org\/10.1056\/NEJM200004203421615 (2000).","journal-title":"N Engl J Med"},{"key":"40457_CR50","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0165-4608(02)00663-5","volume":"141","author":"E McIntyre","year":"2003","unstructured":"McIntyre, E. et al. Multiple endocrine neoplasia type 2A: an unusual clinical presentation and association with renal dysplasia. Cancer Genet Cytogenet 141, 157\u2013159 (2003).","journal-title":"Cancer Genet Cytogenet"},{"key":"40457_CR51","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1101\/gad.1387206","volume":"20","author":"S Jain","year":"2006","unstructured":"Jain, S., Encinas, M., Johnson, E. M. Jr. & Milbrandt, J. Critical and distinct roles for key RET tyrosine docking sites in renal development. Genes Dev 20, 321\u2013333 (2006).","journal-title":"Genes Dev"},{"key":"40457_CR52","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1007\/s00439-012-1181-3","volume":"131","author":"R Chatterjee","year":"2012","unstructured":"Chatterjee, R. et al. Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum Genet 131, 1725\u20131738, https:\/\/doi.org\/10.1007\/s00439-012-1181-3 (2012).","journal-title":"Hum Genet"},{"key":"40457_CR53","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1136\/jmg.2010.088526","volume":"48","author":"C Jeanpierre","year":"2011","unstructured":"Jeanpierre, C. et al. RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects. J Med Genet 48, 497\u2013504, https:\/\/doi.org\/10.1136\/jmg.2010.088526 (2011).","journal-title":"J Med Genet"},{"key":"40457_CR54","doi-asserted-by":"publisher","unstructured":"Capone, V. P., Morello, W., Taroni, F. & Montini, G. Genetics of Congenital Anomalies of the Kidney and Urinary Tract: The Current State of Play. Int J Mol Sci 18, https:\/\/doi.org\/10.3390\/ijms18040796 (2017).","DOI":"10.3390\/ijms18040796"},{"key":"40457_CR55","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/j.mod.2005.03.006","volume":"122","author":"S Kuure","year":"2005","unstructured":"Kuure, S. et al. Crosstalk between Jagged1 and GDNF\/Ret\/GFRalpha1 signalling regulates ureteric budding and branching. Mech Dev 122, 765\u2013780 (2005).","journal-title":"Mech Dev"},{"key":"40457_CR56","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.devcel.2009.07.013","volume":"17","author":"X Chi","year":"2009","unstructured":"Chi, X. et al. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell 17, 199\u2013209 (2009).","journal-title":"Dev Cell"},{"key":"40457_CR57","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1242\/dev.124.20.4077","volume":"124","author":"K Sainio","year":"1997","unstructured":"Sainio, K. et al. Glial-cell-line-derived neurotrophic factor is required for bud initiation from ureteric epithelium. Development 124, 4077\u20134087 (1997).","journal-title":"Development"},{"key":"40457_CR58","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.ydbio.2015.05.023","volume":"404","author":"EN Wainwright","year":"2015","unstructured":"Wainwright, E. N., Wilhelm, D., Combes, A. N., Little, M. H. & Koopman, P. ROBO2 restricts the nephrogenic field and regulates Wolffian duct-nephrogenic cord separation. Dev Biol 404, 88\u2013102, https:\/\/doi.org\/10.1016\/j.ydbio.2015.05.023 (2015).","journal-title":"Dev Biol"},{"key":"40457_CR59","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.ydbio.2006.08.051","volume":"299","author":"MA Basson","year":"2006","unstructured":"Basson, M. A. et al. Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1. Dev Biol 299, 466\u2013477 (2006).","journal-title":"Dev Biol"},{"key":"40457_CR60","doi-asserted-by":"publisher","first-page":"e1000809","DOI":"10.1371\/journal.pgen.1000809","volume":"6","author":"O Michos","year":"2010","unstructured":"Michos, O. et al. Kidney development in the absence of Gdnf and Spry1 requires Fgf10. PLoS Genet 6, e1000809, https:\/\/doi.org\/10.1371\/journal.pgen.1000809 (2010).","journal-title":"PLoS Genet"},{"key":"40457_CR61","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1530\/REP-07-0405","volume":"135","author":"G Dole","year":"2008","unstructured":"Dole, G., Nilsson, E. E. & Skinner, M. K. Glial-derived neurotrophic factor promotes ovarian primordial follicle development and cell-cell interactions during folliculogenesis. Reproduction 135, 671\u2013682, https:\/\/doi.org\/10.1530\/REP-07-0405 (2008).","journal-title":"Reproduction"},{"key":"40457_CR62","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1681\/ASN.2007101098","volume":"19","author":"Z Zhang","year":"2008","unstructured":"Zhang, Z. et al. A common RET variant is associated with reduced newborn kidney size and function. J Am Soc Nephrol 19, 2027\u20132034, https:\/\/doi.org\/10.1681\/ASN.2007101098 (2008).","journal-title":"J Am Soc Nephrol"},{"key":"40457_CR63","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.ajhg.2007.10.008","volume":"82","author":"MA Skinner","year":"2008","unstructured":"Skinner, M. A., Safford, S. D., Reeves, J. G., Jackson, M. E. & Freemerman, A. J. Renal aplasia in humans is associated with RET mutations. Am J Hum Genet 82, 344\u2013351 (2008).","journal-title":"Am J Hum Genet"},{"key":"40457_CR64","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1002\/humu.20705","volume":"29","author":"Y Yang","year":"2008","unstructured":"Yang, Y., Houle, A. M., Letendre, J. & Richter, A. RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec. Hum Mutat 29, 695\u2013702, https:\/\/doi.org\/10.1002\/humu.20705 (2008).","journal-title":"Hum Mutat"},{"key":"40457_CR65","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1089\/gtmb.2016.0079","volume":"20","author":"M Kaczmarczyk","year":"2016","unstructured":"Kaczmarczyk, M. et al. Association Between RET (rs1800860) and GFRA1 (rs45568534, rs8192663, rs181595401, rs7090693, and rs2694770) Variants and Kidney Size in Healthy Newborns. Genet Test Mol Biomarkers 20, 624\u2013628, https:\/\/doi.org\/10.1089\/gtmb.2016.0079 (2016).","journal-title":"Genet Test Mol Biomarkers"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40457-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40457-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40457-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T03:07:00Z","timestamp":1671246420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40457-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,28]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["40457"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-40457-1","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.735417351.793568766","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,28]]},"assertion":[{"value":"9 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 March 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5302"}}