Abstract
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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22 August 2002
Added link to Supplementary Movie A
Notes
NOTE: There is an error in the PDF and upcoming print version of this article. The article is missing a reference to Web Movie A, which should have appeared on the last line of page 30 together with the reference to Web Fig. A.
References
Scott, J.E. Fetal ureteric reflux. Br. J. Urol. 59, 291–296 (1987).
Scott, J.E. & Renwick, M. Antenatal diagnosis of congenital abnormalities in the urinary tract. Results from the Northern Region Fetal Abnormality Survey. Br. J. Urol. 62, 295–300 (1988).
Tanagho, E.A. (ed.) Development of the Ureter (Springer, New York, 1981).
Maizels, M. in Campbell's Urology, Vol. 2 (eds Walsh, P., Retik, A., Darracott Vaughan, E. Jr & Wein, A.) 1545–1600 (W.B. Saunders Company, Philadelphia, 1997).
Schlussel, R.N. & Retik, A.B. in Campbell's Urology, Vol. 2 (eds Walsh, P., Retik, A., Darracott Vaughan, E. Jr & Wein, A.) 1814–1857 (W.B. Saunders Company, Philadelphia, 1997).
Wilson, J.G., Roth, C.V. & Warkany, J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am. J. Anat. 92, 189–217 (1953).
Kastner, P., Mark, M. & Chambon, P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83, 859–869 (1995).
Giguere, V., Fawcett, D., Luo, J., Evans, R.M. & Sucov, H.M. Genetic analysis of the retinoid signal. Ann. NY Acad. Sci. 785, 12–22 (1996).
Zile, M.H. Function of vitamin A in vertebrate embryonic development. J. Nutr. 131, 705–708 (2001).
Wilson, J.G. and Warkany, J. Malformations in the genito-urinary tract induced by maternal vitamin A deficiency in the rat. Am. J. Anat. 83, 357–407 (1948).
Mendelsohn, C. et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120, 2749–2771 (1994).
Batourina, E. et al. Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nature Genet. 27, 74–78 (2001).
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, 380–383 (1994).
Schuchardt, A., D'Agati, V., Pachnis, V. & Costantini, F. Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. Development 122, 1919–1929 (1996).
Srinivas, S. et al. Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. Dev. Genet. 24, 241–251 (1999).
Frazer, J.E. The terminal part of the Wolffian duct. J. Anat. 69, 455–468 (1935).
Meyer, R. Normal and abnormal development of the ureter in the human embryo-a mechanistic consideration. Anat. Rec. 68, 355–371 (1946).
Hutch, J.A. Anatomy and Physiology of the Bladder, Trigone and Urethra (Appleton-Century-Crofts, New York, 1972).
Trupp, M. et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381, 785–789 (1996).
Vega, Q.C., Worby, C.A., Lechner, M.S., Dixon, J.E. & Dressler, G.R. Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc. Natl Acad. Sci. USA 93, 10657–10661 (1996).
Sainio, K. et al. Glial-cell-line-derived neurotrophic factor is required for bud initiation from ureteric epithelium. Development 124, 4077–4087 (1997).
Jing, S. et al. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF. Cell 85, 1113–1124 (1996).
Sanicola, M. et al. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc. Natl Acad. Sci. USA 94, 6238–6243 (1997).
Treanor, J.J. et al. Characterization of a multicomponent receptor for GDNF. Nature 382, 80–83 (1996).
Mendelsohn, C., Batourina, E., Fung, S., Gilbert, T. & Dodd, J. Stromal cells mediate retinoid-dependent functions essential for renal development. Development 126, 1139–1148 (1999).
Sanchez, M.P. et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70–73 (1996).
Vilar, J., Gilbert, T., Moreau, E. & Merlet-Benichou, C. Metanephros organogenesis is highly stimulated by vitamin A derivatives in organ culture. Kidney Int. 49, 1478–1487 (1996).
Dolle, P., Ruberte, E., Leroy, P., Morriss-Kay, G. & Chambon, P. Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development 110, 1133–1151 (1990).
Niederreither, K., Subbarayan, V., Dolle, P. & Chambon, P. Embryonic retinoic acid synthesis is essential for early mouse post- implantation development. Nature Genet. 21, 444–448 (1999).
Schuchardt, A. The role of the c-ret proto-oncogene in the development of the nervous and excretory systems. Thesis, Columbia Univ. (1994).
Srinivas, S., Wu, Z., Chen, C.M., D'Agati, V. & Costantini, F. Dominant effects of RET receptor misexpression and ligand-independent RET signaling on ureteric bud development. Development 126, 1375–1386 (1999).
Ichikawa, I., Kuwayama, F., Pope, J.C., Stephens, F.D. & Miyazaki, Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 61, 889–898 (2002).
Mackie, G.G. & Stephens, F.D. Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J. Urol. 114, 274–280 (1975).
Pope, J.C. IV, Brock, J.W. III, Adams, M.C., Stephens, F.D. & Ichikawa, I. How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J. Am. Soc. Nephrol. 10, 2018–2028 (1999).
Nishimura, H. et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol. Cell 3, 1–10 (1999).
Miyazaki, Y., Oshima, K., Fogo, A., Hogan, B.L. & Ichikawa, I. Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. J. Clin. Invest. 105, 863–873 (2000).
Kume, T., Deng, K. & Hogan, B.L. Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development 127, 1387–1395 (2000).
Pepicelli, C.V., Kispert, A., Rowitch, D.H. & McMahon, A.P. GDNF induces branching and increased cell proliferation in the ureter of the mouse. Dev. Biol. 192, 193–198 (1997).
Tang, M.J., Worley, D., Sanicola, M. & Dressler, G.R. The RET–glial cell-derived neurotrophic factor (GDNF) pathway stimulates migration and chemoattraction of epithelial cells. J. Cell. Biol. 142, 1337–1345 (1998).
Clendenon, J.L., Phillips, C.L., Sandoval, R.M., Fang, S. & Dunn, K.W. Voxx: a PC-based, near real-time volume rendering system for biological microscopy. Am. J. Physiol. Cell Physiol. 282, C213–C218 (2002).
Acknowledgements
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.).
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Batourina, E., Choi, C., Paragas, N. et al. Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet 32, 109–115 (2002). https://doi.org/10.1038/ng952
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DOI: https://doi.org/10.1038/ng952
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