Almost 1% of human infants are born with urogenital abnormalities, many of which are linked to irregular connections between the distal ureters and the bladder. During development, ureters migrate by an unknown mechanism from their initial integration site in the Wolffian ducts up to the base of the bladder in a process that we call ureter maturation. Rara−/−Rarb2−/− mice display impaired vitamin A signaling and develop syndromic urogenital malformations similar to those that occur in humans, including renal hypoplasia, hydronephrosis and mega-ureter, abnormalities also seen in mice with mutations in the proto-oncogene Ret. Here we show that ureter maturation depends on formation of the 'trigonal wedge', a newly identified epithelial outgrowth from the base of the Wolffian ducts, and that the distal ureter abnormalities seen in Rara−/−Rarb2−/− and Ret−/− mutant mice are probably caused by a failure of this process. Our studies indicate that formation of the trigonal wedge may be essential for correct insertion of the distal ureters into the bladder, and that these events are mediated by the vitamin A and Ret signaling pathways.
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We thank Q. Al-Awqati, D. Herzlinger, R. Hen, C. Olsson, U. Grieshammer and G. Martin for discussions and critical reading of the manuscript, and P. Chambon and S. Srinivas for mice. This work was supported by grants from the US National Institutes of Health (to C.L.M., F.D.C. and R.B.) and by a fellowship from the New York Academy of Medicine (to C.L.M.).