Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6.
Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9016-E9025. doi: 10.1073/pnas.1707229114. Epub 2017 Oct 9.
The elimination of unwanted cells by apoptosis is necessary for tissue morphogenesis. However, the cellular control of morphogenetic apoptosis is poorly understood, notably the modulation of cell sensitivity to apoptotic stimuli. Ureter maturation, the process by which the ureter is displaced to the bladder wall, represents an exquisite example of morphogenetic apoptosis, requiring the receptor protein tyrosine phosphatases (RPTPs): LAR and RPTPσ. Here we show that LAR-RPTPs act through cellular inhibitor of apoptosis protein 1 (cIAP1) to modulate caspase 3,7-mediated ureter maturation. Pharmacologic or genetic inactivation of cIAP1 reverts the apoptotic deficit of LAR-RPTP-deficient embryos. Moreover, (cIAP1) inactivation generates excessive apoptosis leading to vesicoureteral reflux in newborns, which underscores the importance of apoptotic modulation during urinary tract morphogenesis. We finally demonstrate that LAR-RPTP deficiency increases cIAP1 stability during apoptotic cell death. Together these results identify a mode of cIAP1 regulation playing a critical role in the cellular response to apoptotic pathway activation in the embryo.
细胞凋亡可消除多余细胞，这对于组织形态发生是必需的。然而，形态发生性细胞凋亡的细胞控制还了解甚少，特别是细胞对凋亡刺激敏感性的调节。输尿管成熟是输尿管向膀胱壁移位的过程，它代表了形态发生性细胞凋亡的一个极好例子，需要受体蛋白酪氨酸磷酸酶（RPTPs）：LAR 和 RPTPσ。在这里，我们表明 LAR-RPTP 通过细胞凋亡抑制蛋白 1（cIAP1）起作用，以调节半胱天冬酶 3、7 介导的输尿管成熟。药理学或遗传失活 cIAP1 可恢复 LAR-RPTP 缺陷胚胎的凋亡缺陷。此外，cIAP1 的失活会导致新生动物过度凋亡，从而导致输尿管反流，这突出表明在尿路形态发生过程中凋亡调节的重要性。我们最后证明 LAR-RPTP 缺陷会增加凋亡细胞死亡过程中 cIAP1 的稳定性。这些结果共同确定了 cIAP1 调节的一种模式，它在胚胎中对细胞对凋亡途径激活的反应中起着关键作用。
