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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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Research Article Development

Maturation of ureter-bladder connection in mice is controlled by LAR family receptor protein tyrosine phosphatases

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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 1

Craniofacial anomalies in Ptprs;Ptprf double-mutant embryos.

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Craniofacial anomalies in Ptprs;Ptprf double-mutant embryos.
   
(A–C) G...
(A–C) Gross morphological appearance of control (A) and Ptprs–/–PtprfΔP/ΔP (B and C) embryos at E18.5. Note the presence of micrognathia (arrow), exencephaly (arrowhead) and open eyelid (open arrowhead) in Ptprs–/–PtprfΔP/ΔP embryos. (D and E) Coronal sections of the face region of control (D) and Ptprs–/–PtprfΔP/ΔP (E) embryos stained by H&E. The tongue and palate of control embryos were readily distinguishable, whereas Ptprs–/–PtprfΔP/ΔP embryos showed smaller lower jaw (arrowhead) and an opened palate (open arrowhead) at an equivalent level of the head. (F–I) Coronal sections of the eye of control (F and H) and Ptprs–/–PtprfΔP/ΔP (G and I) embryos stained by H&E. In contrast to the characteristic eye morphology observed in control embryos, Ptprs–/–PtprfΔP/ΔP eyes sometimes showed a hyperplastic inner nuclear layer (single asterisk in G) and abnormal retrolental tissue (indicated by dotted line in I) filling the hyaloid cavity. (H and I) High-magnification views of the boxes in F and G. (I) In Ptprs–/–PtprfΔP/ΔP embryos, neuroretinal lamination was disorganized (arrows). Note the presence of pigmented cells (white arrowheads), the hyaloid artery within the retrolental tissue (double asterisk), and the lens degradation (black arrowhead). Scale bars: 1 mm (A–G) and 10 μm (H and I). ONL, outer nuclear layer; INL, inner nuclear layer.
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