Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter
Yoichi Miyazaki, … , Brigid L.M. Hogan, Iekuni Ichikawa
Yoichi Miyazaki, … , Brigid L.M. Hogan, Iekuni Ichikawa
Published April 1, 2000
Citation Information: J Clin Invest. 2000;105(7):863-873. https://doi.org/10.1172/JCI8256.
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Article

Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter

Abstract

In the normal mouse embryo, Bmp4 is expressed in mesenchymal cells surrounding the Wolffian duct (WD) and ureter stalk, whereas bone morphogenetic protein (BMP) type I receptor genes are transcribed either ubiquitously (Alk3) or exclusively in the WD and ureter epithelium (Alk6). Bmp4 heterozygous null mutant mice display, with high penetrance, abnormalities that mimic human congenital anomalies of the kidney and urinary tract (CAKUT), including hypo/dysplastic kidneys, hydroureter, ectopic ureterovesical (UV) junction, and double collecting system. Analysis of mutant embryos suggests that the kidney hypo/dysplasia results from reduced branching of the ureter, whereas the ectopic UV junction and double collecting system are due to ectopic ureteral budding from the WD and accessory budding from the main ureter, respectively. In the cultured metanephros deprived of sulfated glycosaminoglycans (S-GAGs), BMP4-loaded beads partially rescue growth and elongation of the ureter. By contrast, when S-GAGs synthesis is not inhibited, BMP4 beads inhibit ureter branching and expression of Wnt 11, a target of glial cell-derived neurotrophic factor signaling. Thus, Bmp4 has 2 functions in the early morphogenesis of the kidney and urinary tract. One is to inhibit ectopic budding from the WD or the ureter stalk by antagonizing inductive signals from the metanephric mesenchyme to the illegitimate sites on the WD. The other is to promote the elongation of the branching ureter within the metanephros, thereby promoting kidney morphogenesis.

Authors

Yoichi Miyazaki, Keisuke Oshima, Agnes Fogo, Brigid L.M. Hogan, Iekuni Ichikawa

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Figure 9

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BMP4 downregulates the expression of Wnt 11 in metanephric explants. (a–...
BMP4 downregulates the expression of Wnt 11 in metanephric explants. (a–d) The explants are incubated for 48 hours (a and b) or 72 hours (c and d) with BMP4 beads (b and d) or control BSA beads (a and c) that have been placed adjacent to the secondary buds and subjected to Pax2 whole-mount in situ hybridization. Branching is inhibited in the area surrounding the bead. (e–h) Wnt 11 expression in the explants incubated with BMP4 beads for 0 hours (e), 8 hours (f), and 16 hours (g) or control beads for 16 hours (h). Wnt 11 expression almost disappeared at the ureter epithelium around the BMP4 beads, as indicated by arrowheads. (i–l) Expression of GDNF in the explants treated with BMP4-beads for 0 hours (i), 8 hours (j), and 16 hours (k) or control beads for 16 hours (l). GDNF expression is almost comparable between the areas surrounding BSA- and BMP4-soaked beads. Dashed circles indicate the location of the beads. Bar, 300 μm.