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.
View: Text | PDF
Research Article Development

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

×

Figure 4

Apoptotic cell death in CND.

Options: View larger image (or click on image) Download as PowerPoint
Apoptotic cell death in CND. (A) Schematic representation of sagittal vi...
(A) Schematic representation of sagittal view of a urogenital system at E12.5. Dotted lines indicate the position of sections shown in B–G. (B–G) TUNEL stain (red) and anti-Pax2 counterstain (green) on transverse sections of E12.5 embryos derived from control (B–D) and Ptprs–/–PtprfΔP/ΔP embryos (E–G). CNDs were separated into 3 sections: rostral CND (closest to ureter), middle CND, and caudal CND (closest to bladder). (H) Schematic representation of sagittal view of normal urogenital system at E14.0. (I and J) TUNEL stain (red) and anti-Pax2 counterstain (green) on sagittal sections of E14.0 control (I) and Ptprs–/–PtprfΔP/ΔP (J) urogenital systems. Dotted lines outline the cloaca epithelium. (K–M) Quantitative analysis of the cell death observed in control and Ptprs–/–PtprfΔP/ΔP CNDs. (K) Control embryos showed a strong increase in apoptosis along the rostrocaudal axis of the CND (TUNEL-positive/Pax-2–positive; n = 8 CNDs). In contrast, Ptprs–/–PtprfΔP/ΔP embryos showed a reduction in apoptotic cell death (n = 8 CNDs). (L) Quantitative analysis of caspase-3–positive cells showed a reduction in activated caspase-3–positive signals in the middle and caudal CND of Ptprs–/–PtprfΔP/ΔP embryos (n = 4 CNDs for each genotype). (M) Quantitative analysis of activated caspase-8–positive cells. No significant difference was detected between control and Ptprs–/–PtprfΔP/ΔP embryos (n = 6 CNDs for each genotype). Scale bars: 10 μm. The results shown are means ± SD.