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


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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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 information

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).

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