{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:16:34Z","timestamp":1778170594751,"version":"3.51.4"},"reference-count":34,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T00:00:00Z","timestamp":1543795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GE 539\/13"],"award-info":[{"award-number":["GE 539\/13"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2019,3,15]]},"abstract":"<jats:p>Wilms tumor (WT) is the most common kidney cancer in childhood. Mutations in the microprocessor genes <jats:italic>DROSHA<\/jats:italic> and <jats:italic>DGCR8<\/jats:italic> have been identified as putative oncogenic drivers, indicating a critical role of aberrant miRNA processing in WT formation. To characterize the <jats:italic>in vivo<\/jats:italic> role of <jats:italic>DROSHA<\/jats:italic> mutations during kidney development and their oncogenic potential, we analyzed mouse lines with either a targeted deletion of <jats:italic>Drosha<\/jats:italic> or an inducible expression of human <jats:italic>DROSHA<\/jats:italic> carrying a tumor\u2010specific E1147K mutation that acts in a dominant negative manner. Both types of mutation induce striking changes in miRNA patterns. Six2\u2010cre mediated deletion of <jats:italic>Drosha<\/jats:italic> in nephron progenitors led to perinatal lethality with apoptotic loss of progenitor cells and early termination of nephrogenesis. Mosaic deletions <jats:italic>via<\/jats:italic> Wt1\u2010cre<jats:sup>ERT2<\/jats:sup> resulted in a milder phenotype with viable offspring that developed proteinuria after 2\u20134 weeks, but no evidence of tumor formation. Activation of the <jats:italic>DROSHA<\/jats:italic>\u2010<jats:italic>E1147K<\/jats:italic> transgene <jats:italic>via<\/jats:italic> Six2\u2010cre, on the other hand, induced a more severe phenotype with apoptosis of progenitor cells, proteinuria and glomerular sclerosis. The severely growth retarded mice died within the first 2 months of life, confirming the predicted dominant\u2010negative effect of <jats:italic>DROSHA\u2010E1147K in vivo<\/jats:italic>. While our data underscores the importance of a viable self\u2010renewing progenitor pool for kidney development, there was no evidence of tumor formation through impaired DROSHA function. This suggests that either additional alterations in mitogenic or antiapoptotic pathways are needed for malignant transformation, or premature loss of a susceptible target cell population and early lethality prevent WT formation.<\/jats:p>","DOI":"10.1002\/ijc.31952","type":"journal-article","created":{"date-parts":[[2018,10,27]],"date-time":"2018-10-27T07:04:56Z","timestamp":1540623896000},"page":"1391-1400","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Loss or oncogenic mutation of <i>DROSHA<\/i> impairs kidney development and function, but is not sufficient for Wilms tumor formation"],"prefix":"10.1002","volume":"144","author":[{"given":"Philip","family":"Kruber","sequence":"first","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry Wuerzburg University  Wuerzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oguzhan","family":"Angay","sequence":"additional","affiliation":[{"name":"Rudolf Virchow Center, Research Center for Experimental Biomedicine University of W\u00fcrzburg  W\u00fcrzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Winkler","sequence":"additional","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry Wuerzburg University  Wuerzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"B\u00f6sl","sequence":"additional","affiliation":[{"name":"Department of Experimental Biomedicine University Hospital and Rudolf Virchow Center, University of W\u00fcrzburg  W\u00fcrzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Kneitz","sequence":"additional","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Physiological Chemistry Wuerzburg University  Wuerzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin G.","family":"Heinze","sequence":"additional","affiliation":[{"name":"Rudolf Virchow Center, Research Center for Experimental Biomedicine University of W\u00fcrzburg  W\u00fcrzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7915-6045","authenticated-orcid":false,"given":"Manfred","family":"Gessler","sequence":"additional","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry Wuerzburg University  Wuerzburg Germany"},{"name":"Comprehensive Cancer Center Mainfranken Wuerzburg University  Wuerzburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,12,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103175"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600491"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.05.001"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03868"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.01.002"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5802"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5039"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.01.003"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.06032.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm475"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1181"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1063"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv403"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.119.4.1329"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(98)00072-0"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.010"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-0436.2003.710301.x"},{"key":"e_1_2_6_20_1","doi-asserted-by":"crossref","unstructured":"SommerC StraehleC K\u00f6theU et al. ilastik: Interactive learning and segmentation toolkit. 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