Maturation of ureter-bladder connection in mice is controlled by LAR family receptor protein tyrosine phosphatases
Noriko Uetani, … , Michel L. Tremblay, Maxime Bouchard
Noriko Uetani, … , Michel L. Tremblay, Maxime Bouchard
Published March 9, 2009
Citation Information: J Clin Invest. 2009;119(4):924-935. https://doi.org/10.1172/JCI37196.
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Maturation of ureter-bladder connection in mice is controlled by LAR family receptor protein tyrosine phosphatases

Abstract

Congenital anomalies affecting the ureter-bladder junction are frequent in newborns and are often associated with other developmental defects. However, the molecular and morphological processes underlying these malformations are still poorly defined. In this study, we identified the leukocyte antigen–related (LAR) family protein tyrosine phosphatase, receptor type, S and F (Ptprs and Ptprf [also known as Lar], respectively), as crucially important for distal ureter maturation and craniofacial morphogenesis in the mouse. Embryos lacking both Ptprs and Ptprf displayed severe urogenital malformations, characterized by hydroureter and ureterocele, and craniofacial defects such as cleft palate, micrognathia, and exencephaly. The detailed analysis of distal ureter maturation, the process by which the ureter is displaced toward its final position in the bladder wall, leads us to propose a revised model of ureter maturation in normal embryos. This process was deficient in embryos lacking Ptprs and Ptprf as a result of a marked reduction in intrinsic programmed cell death, thereby causing urogenital system malformations. In cell culture, Ptprs bound and negatively regulated the phosphorylation and signaling of the Ret receptor tyrosine kinase, whereas Ptprs-induced apoptosis was inhibited by Ret expression. Together, these results suggest that ureter positioning is controlled by the opposing actions of Ret and LAR family phosphatases regulating apoptosis-mediated tissue morphogenesis.

Authors

Noriko Uetani, Kristen Bertozzi, Melanie J. Chagnon, Wiljan Hendriks, Michel L. Tremblay, Maxime Bouchard

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Figure 3

Distal ureter maturation defects in Ptprs–/–PtprfΔP/ΔP embryos.

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Distal ureter maturation defects in Ptprs–/–PtprfΔP/ΔP embryos. Top:...
Top: Diagrams of WT E11.5–E15.5 urogenital systems. (A–H) H&E-stained sagittal sections of representative control (A–D) and Ptprs–/–PtprfΔP/ΔP urogenital systems (E–H) at different developmental stages. At E11.5, no difference in CND length was observed between control (A) and Ptprs–/–PtprfΔP/ΔP embryos (E). CND length is indicated by dotted lines, distal ureter is indicated by solid lines. At E13.5 (B and F) and E14.5 (C and G), the distal ureter was in close apposition with the bladder epithelium in control embryos (B and C). In contrast, Ptprs–/–PtprfΔP/ΔP embryos harbored a distal ureter located away from the bladder (F and G). (D and H) At E15.5, distal ureter elimination allowed the ureter to reconnect into bladder (dotted white circle) in a normal control (D), while the distal ureter remained at a distance from the bladder epithelium in Ptprs–/–PtprfΔP/ΔP embryos (H). (I) Length of CNDs was quantified at different developmental stages. Although there was no difference in CND lengths at E11.5, the CND was significantly longer in Ptprs–/–PtprfΔP/ΔP at E12.5 and E13.5. Error bars indicate SEM. (J–M) In situ hybridization on E12.5 transversal sections using antisense cRNA probes against Ptprf (J), Ptprs (K), Ptprd (L), and a sense probe against Ptprs (M). (J) Ptprf expression was mostly restricted to the CND, while Ptprs expression was detected ubiquitously in the mesenchyme and cloaca epithelium (K). (L) Ptprd was predominantly expressed in the mesenchyme. (M) A sense Ptprs probe was used as negative control. Scale bars: 10 μm. ND, nephric duct; dUr, distal ureter; CE, cloaca epithelium.