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 1

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Expression of Bmp4 and BMP type 1 receptor genes during kidney and urina...
Expression of Bmp4 and BMP type 1 receptor genes during kidney and urinary tract development. Two adjacent sections from E10.5 (a, b, and g–j), E12.5 (c, d, and k–n) and E14.5 (e and f) embryos were processed for (left) H&E staining and (right) in situ hybridization of Bmp4 (b, d, and f), Alk3 (h and l), or Alk6 (j and n). (a and b) Bmp4 is expressed in the mesenchymal cells surrounding the WD (arrowheads), but not in MM and WD per se. (c and d) Bmp4 expression is seen around the branching ureter and ureter stalk, but not in the MM. (e and f) In addition to the expression in the stromal mesenchyme, Bmp4 mRNA is distributed in the S-shaped bodies (arrowheads) and the prospective smooth muscle layer along the ureter. (g, h, k, and l) Expression of Alk3 is essentially ubiquitous, but noticeably intense in WD and the branching ureter (arrowheads in h and l). (i, j, m, and n) Alk6 transcripts are exclusively present in the WD and the ureter epithelium (arrowheads in j and n). WD, Wolffian duct; MM, metanephric mesenchyme; Ut, ureter; BUt, branching ureter within the kidney. Bar, 200 μm.