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Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder

Abstract

Removal of toxic substances from the blood depends on patent connections between the kidney, ureters and bladder that are established when the ureter is transposed from its original insertion site in the male genital tract to the bladder. This transposition is thought to occur as the trigone forms from the common nephric duct and incorporates into the bladder. Here we re-examine this model in the context of normal and abnormal development. We show that the common nephric duct does not differentiate into the trigone but instead undergoes apoptosis, a crucial step for ureter transposition controlled by vitamin A–induced signals from the primitive bladder. Ureter abnormalities occur in 1–2% of the human population and can cause obstruction and end-stage renal disease. These studies provide an explanation for ureter defects underlying some forms of obstruction in humans and redefine the current model of ureter maturation.

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Figure 1: The current model of ureter maturation.
Figure 2: The CND undergoes remodeling as it inserts into the urogenital sinus.
Figure 3: The CND does not differentiate into the bladder trigone.
Figure 4: The CND undergoes apoptosis during ureter maturation, in close contact with the sinus ridge.
Figure 5: Vitamin A–dependent signals from the urogenital sinus regulate CND apoptosis.
Figure 6: The urogenital sinus generates a source of signals that control CND apoptosis.
Figure 7: A new model of ureter maturation.

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References

  1. Tanagho, E.A. Development of the Ureter (Springer, New York, 1981).

    Book  Google Scholar 

  2. Meyer, R. Normal and abnormal development of the ureter in the human embryo-a mechanistic consideration. Anat. Rec. 68, 355–371 (1946).

    Article  Google Scholar 

  3. Hutch, J.A. Anatomy and Physiology of the Bladder, Trigone and Urethra (Butterworth's Appleton-Century-Crofts, London, New York, 1972).

    Google Scholar 

  4. Wilson, J.G. & Warkany, J. Malformations in the genito-urinary tract induced by maternal vitamin A deficiency in the rat. Am. J. Anat. 83, 357–407 (1948).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Mangelsdorf, D.J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Duester, G., Mic, F.A. & Molotkov, A. Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Chem. Biol. Interact. 143–144, 201–210 (2003).

    Article  PubMed  Google Scholar 

  8. Napoli, J.L. Retinoic acid: its biosynthesis and metabolism. Prog. Nucleic Acid Res. Mol. Biol. 63, 139–188 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Batourina, E. et al. Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat. Genet. 32, 109–115 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Yu, J., Carroll, T.J. & McMahon, A.P. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development 129, 5301–5312 (2002).

    CAS  PubMed  Google Scholar 

  12. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Yucel, S. & Baskin, L.S. An anatomical description of the male and female urethral sphincter complex. J. Urol. 171, 1890–1897 (2004).

    Article  PubMed  Google Scholar 

  14. Bok, G. & Drews, U. The role of the Wolffian ducts in the formation of the sinus vagina: an organ culture study. J. Embryol. Exp. Morphol. 73, 275–295 (1983).

    CAS  PubMed  Google Scholar 

  15. Mauch, R.B., Thiedemann, K.U. & Drews, U. The vagina is formed by downgrowth of Wolffian and Mullerian ducts. Graphical reconstructions from normal and Tfm mouse embryos. Anat. Embryol. (Berl.) 172, 75–87 (1985).

    Article  CAS  Google Scholar 

  16. Watanabe, T. & Costantini, F. Real-time analysis of ureteric bud branching morphogenesis in vitro . Dev. Biol. 271, 98–108 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Niederreither, K., McCaffery, P., Drager, U.C., Chambon, P. & Dolle, P. Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mech. Dev. 62, 67–78 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Dickman, E.D., Thaller, C. & Smith, S.M. Temporally-regulated retinoic acid depletion produces specific neural crest, ocular and nervous system defects. Development 124, 3111–3121 (1997).

    CAS  PubMed  Google Scholar 

  19. Niederreither, K., Subbarayan, V., Dolle, P. & Chambon, P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat. Genet. 21, 444–448 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Mic, F.A., Haselbeck, R.J., Cuenca, A.E. & Duester, G. Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development 129, 2271–2282 (2002).

    CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. Stephens, F.D. Congenital Malformations of the Urinary Tract (Praeger, New York, 1983).

    Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Thomas, J.C., Demarco, R.T. & Pope, J.C. Molecular biology of ureteral bud and trigonal development. Curr. Urol. Rep. 6, 146–151 (2005).

    Article  PubMed  Google Scholar 

  25. Kochhar, D.M., Jiang, H., Penner, J.D., Beard, R.L. & Chandraratna, A.S. Differential teratogenic response of mouse embryos to receptor selective analogs of retinoic acid. Chem. Biol. Interact. 100, 1–12 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Willhite, C.C., Lovey, A. & Eckhoff, C. Distribution, teratogenicity, and embryonic delivered dose of retinoid ro 23–9223. Toxicol. Appl. Pharmacol. 164, 171–175 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Yasuda, Y. et al. Developmental anomalies induced by all-trans retinoic acid in fetal mice: I. Macroscopic findings. Teratology 34, 37–49 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Shakya, R., Watanabe, T. & Costantini, F. The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev. Cell 8, 65–74 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Basson, M.A. et al. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev. Cell 8, 229–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Grieshammer, U. et al. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev. Cell 6, 709–717 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

  32. Brophy, P.D., Ostrom, L., Lang, K.M. & Dressler, G.R. Regulation of ureteric bud outgrowth by Pax2-dependent activation of the glial derived neurotrophic factor gene. Development 128, 4747–4756 (2001).

    CAS  PubMed  Google Scholar 

  33. Yu, O.H., Murawski, I.J., Myburgh, D.B. & Gupta, I.R. Overexpression of RET leads to vesicoureteric reflux in mice. Am. J. Physiol. Renal Physiol. 287, F1123–F1130 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    CAS  PubMed  Google Scholar 

  36. Larsen, W.J., Sherman, L.S., Potter, S.S. & Scott, W.J. Human Embryology (Churchill Livingstone, New York, 2001).

    Google Scholar 

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Acknowledgements

We thank L. Spraggon, H. Sun, Q. Al-awqati, D. Herzlinger, K. Glassberg and F. Costantini for critical reading of the manuscript and discussions; P. Chambon and P. Dolle for the Raldh2 mutants; F. Costantini for the Hoxb7-Gfp line and for help with time-lapse experiments; and G. Cook for artwork. This work was supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases to C.L.M. and A.P.M.

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Correspondence to Cathy L Mendelsohn.

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Supplementary Video 1

CND apoptosis is crucial for separation of the ureter orifice from the Wolffian duct. Ureter maturation visualized by time-lapse photography. E12 Hoxb7-Gfp urogenital blocks were cultured for 60h and photographed at 1-hour intervals with an automatic shutter. Digital jpg images were then converted to an MPEG movie. Note the presence of apoptotic cells that undergo shape changes in the CND prior to ureter transposition. (MOV 7127 kb)

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Batourina, E., Tsai, S., Lambert, S. et al. Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder. Nat Genet 37, 1082–1089 (2005). https://doi.org/10.1038/ng1645

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