Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraβe 108, 01307 Dresden, Germany.
Dev Cell. 2023 Jan 23;58(2):139-154.e8. doi: 10.1016/j.devcel.2022.12.006.
WNT signaling is important in development, stem cell maintenance, and disease. WNT ligands typically signal via receptor activation across the plasma membrane to induce β-catenin-dependent gene activation. Here, we show that in mammalian primary cilia, WNT receptors relay a WNT/GSK3 signal that β-catenin-independently promotes ciliogenesis. Characterization of a LRP6 ciliary targeting sequence and monitoring of acute WNT co-receptor activation (phospho-LRP6) support this conclusion. Ciliary WNT signaling inhibits protein phosphatase 1 (PP1) activity, a negative regulator of ciliogenesis, by preventing GSK3-mediated phosphorylation of the PP1 regulatory inhibitor subunit PPP1R2. Concordantly, deficiency of WNT/GSK3 signaling by depletion of cyclin Y and cyclin-Y-like protein 1 induces primary cilia defects in mouse embryonic neuronal precursors, kidney proximal tubules, and adult mice preadipocytes.
WNT 信号通路在发育、干细胞维持和疾病中都具有重要作用。WNT 配体通常通过跨质膜的受体激活来传递信号，从而诱导 β-连环蛋白依赖性基因激活。在这里，我们表明在哺乳动物初级纤毛中，WNT 受体传递 WNT/GSK3 信号，该信号独立于 β-连环蛋白促进纤毛发生。LRP6 纤毛靶向序列的表征和急性 WNT 共受体激活（磷酸化 LRP6）的监测支持这一结论。纤毛 WNT 信号通过防止 GSK3 介导的磷酸化 PPP1R2 调节抑制亚单位 PP1，抑制蛋白磷酸酶 1（PP1）的活性，从而抑制纤毛发生。一致地，通过耗尽 cyclin Y 和 cyclin-Y 样蛋白 1 来抑制 WNT/GSK3 信号，会导致小鼠胚胎神经元前体细胞、肾脏近端小管和成年小鼠前脂肪细胞中的初级纤毛缺陷。
