Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Department of Internal Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Curr Biol. 2017 Oct 23;27(20):3120-3131.e4. doi: 10.1016/j.cub.2017.09.011. Epub 2017 Oct 12.
Oriented cell division (OCD) and convergent extension (CE) shape developing renal tubules, and their disruption has been associated with polycystic kidney disease (PKD) genes, the majority of which encode proteins that localize to primary cilia. Core planar cell polarity (PCP) signaling controls OCD and CE in other contexts, leading to the hypothesis that disruption of PCP signaling interferes with CE and/or OCD to produce PKD. Nonetheless, the contribution of PCP to tubulogenesis and cystogenesis is uncertain, and two major questions remain unanswered. Specifically, the inference that mutation of PKD genes interferes with PCP signaling is untested, and the importance of PCP signaling for cystogenic PKD phenotypes has not been examined. We show that, during proliferative stages, PCP signaling polarizes renal tubules to control OCD. However, we find that, contrary to the prevailing model, PKD mutations do not disrupt PCP signaling but instead act independently and in parallel with PCP signaling to affect OCD. Indeed, PCP signaling that is normally downregulated once development is completed is retained in cystic adult kidneys. Disrupting PCP signaling results in inaccurate control of tubule diameter, a tightly regulated parameter with important physiological ramifications. However, we show that disruption of PCP signaling is not cystogenic. Our results suggest that regulating tubule diameter is a key function of PCP signaling but that loss of this control does not induce cysts.
定向细胞分裂（OCD）和会聚延伸（CE）塑造了发育中的肾小管，其破坏与多囊肾病（PKD）基因有关，这些基因大多编码定位于初级纤毛的蛋白质。核心平面细胞极性（PCP）信号控制着其他情况下的 OCD 和 CE，这导致了这样一种假设，即 PCP 信号的破坏干扰了 CE 和/或 OCD，从而产生 PKD。尽管如此，PCP 对肾小管发生和囊肿发生的贡献仍不确定，仍有两个主要问题尚未得到解答。具体来说，PKD 基因突变干扰 PCP 信号的推断尚未得到检验，PCP 信号对囊肿发生 PKD 表型的重要性也尚未得到检验。我们表明，在增殖阶段，PCP 信号会使肾脏小管极化以控制 OCD。然而，我们发现，与流行的模型相反，PKD 突变并没有破坏 PCP 信号，而是独立于 PCP 信号并与之平行作用以影响 OCD。事实上，在发育完成后通常会下调的 PCP 信号在囊性成年肾脏中仍被保留。破坏 PCP 信号会导致对小管直径的控制不准确，而小管直径是一个受严格调控的参数，具有重要的生理后果。然而，我们表明破坏 PCP 信号不是囊肿发生的原因。我们的结果表明，调节小管直径是 PCP 信号的一个关键功能，但失去这种控制并不会诱导囊肿。
