Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton.
Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton.
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DOI：
10.1371/journal.pbio.1001720
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发表时间：
2013-11
期刊：
影响因子：
9.8
通讯作者：
Lo CW
中科院分区：
文献类型：
--
作者：
Cui C;Chatterjee B;Lozito TP;Zhang Z;Francis RJ;Yagi H;Swanhart LM;Sanker S;Francis D;Yu Q;San Agustin JT;Puligilla C;Chatterjee T;Tansey T;Liu X;Kelley MW;Spiliotis ET;Kwiatkowski AV;Tuan R;Pazour GJ;Hukriede NA;Lo CW
Wdpcp是平面细胞极性和纤毛发生所需的蛋白质，通过直接调节肌动蛋白细胞骨架来调节细胞极性和排列。平面细胞极性（PCP）调节胚胎发育过程中集体细胞运动所需的细胞排列。这需要PCP/PCP效应蛋白，其中一些也发挥重要作用，在纤毛发生，突出了长期存在的问题，纤毛在PCP中的作用。Wdpcp是一种PCP效应物，最近被证明可以调节纤毛发生和集体细胞运动，但其潜在机制尚不清楚。在这里，我们表明Wdpcp可以通过直接调节肌动蛋白细胞骨架来调节PCP。通过恢复Wdpcp突变小鼠模型，使这些研究成为可能。Wdpcp缺陷小鼠表现出令人联想到Bardet-Biedl/Meckel-Gruber纤毛病变综合征的表型，包括与PCP扰动相关的心脏流出道和耳蜗缺陷。我们观察到Wdpcp定位于过渡区，并且在Wdpcp缺陷的细胞中，Sept 2、Nphp 1和Mks 1从过渡区丢失，表明Wdpcp是招募纤毛发生所必需的蛋白质所必需的。Wdpcp也存在于细胞质中，它位于肌动蛋白细胞骨架和粘着斑中。Wdpcp与Sept 2相互作用，并与Sept 2共定位在肌动蛋白丝中，但在Wdpcp缺陷细胞中，Sept 2从肌动蛋白细胞骨架中丢失，表明Wdpcp是Sept 2招募到肌动蛋白丝所必需的。值得注意的是，组织的肌动蛋白丝和重点接触显着改变Wdpcp缺陷细胞。这与膜皱褶减少、未能建立细胞极性和定向细胞迁移丧失有关。这些结果表明Wdpcp突变体中的PCP缺陷不是由纤毛损失引起的，而是由肌动蛋白细胞骨架的直接破坏引起的。与此一致，Wdpcp突变耳蜗具有正常的动纤毛，但表现出PCP缺陷。总之，这些研究结果提供了第一个证据，据我们所知，纤毛发生所需的PCP成分可以直接调节肌动蛋白细胞骨架，以调节细胞极性和定向细胞迁移。纤毛是微观细胞表面的毛发状突起，可以作为天线来介导细胞信号。破坏纤毛发生的突变可导致许多与称为“纤毛病”的综合征相关的发育异常。一些发育缺陷，如肢体多指（趾），是由于纤毛转导的音刺猬信号的破坏引起的，而其他缺陷，如内耳毛细胞的异常模式，是由于Wnt信号的破坏导致平面细胞极性（PCP）的调节-细胞极化和排列的过程。虽然纤毛病变表型表明纤毛参与调节PCP，但纤毛与PCP之间的机制联系一直难以捉摸。我们的研究使用携带突变的Wdpcp，纤毛发生和PCP所需的基因的小鼠模型表明，Wdpcp调制PCP涉及与肌动蛋白细胞骨架的相互作用，从其功能的纤毛发生。我们观察到Wdpcp在纤毛中的定位，在那里它是必要的纤毛发生的蛋白质的招聘。Wdpcp与Sept 2相互作用，也存在于肌动蛋白丝中，在那里它调节PCP所必需的肌动蛋白动力学。总之，这些研究结果表明，PCP调节Wdpcp是不同的，其功能在纤毛发生，并涉及直接调制的肌动蛋白细胞骨架。
Wdpcp, a protein required for both planar cell polarity and ciliogenesis, regulates cell polarity and alignment via direct modulation of the actin cytoskeleton. Planar cell polarity (PCP) regulates cell alignment required for collective cell movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question of the role of the cilium in PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and collective cell movement, but the underlying mechanism is unknown. Here we show Wdpcp can regulate PCP by direct modulation of the actin cytoskeleton. These studies were made possible by recovery of a Wdpcp mutant mouse model. Wdpcp-deficient mice exhibit phenotypes reminiscent of Bardet–Biedl/Meckel–Gruber ciliopathy syndromes, including cardiac outflow tract and cochlea defects associated with PCP perturbation. We observed Wdpcp is localized to the transition zone, and in Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the transition zone, indicating Wdpcp is required for recruitment of proteins essential for ciliogenesis. Wdpcp is also found in the cytoplasm, where it is localized in the actin cytoskeleton and in focal adhesions. Wdpcp interacts with Sept2 and is colocalized with Sept2 in actin filaments, but in Wdpcp-deficient cells, Sept2 was lost from the actin cytoskeleton, suggesting Wdpcp is required for Sept2 recruitment to actin filaments. Significantly, organization of the actin filaments and focal contacts were markedly changed in Wdpcp-deficient cells. This was associated with decreased membrane ruffling, failure to establish cell polarity, and loss of directional cell migration. These results suggest the PCP defects in Wdpcp mutants are not caused by loss of cilia, but by direct disruption of the actin cytoskeleton. Consistent with this, Wdpcp mutant cochlea has normal kinocilia and yet exhibits PCP defects. Together, these findings provide the first evidence, to our knowledge, that a PCP component required for ciliogenesis can directly modulate the actin cytoskeleton to regulate cell polarity and directional cell migration. Cilia are microscopic cell surface hair-like protrusions that can act as antennae to mediate cell signaling. Mutations disrupting ciliogenesis can cause many developmental anomalies associated with syndromes known as “ciliopathies.” Some developmental defects, such as limb polydactyly, arise from disruption of cilia-transduced sonic hedgehog signaling, while other defects, such as aberrant patterning of hair cells in the inner ear, arise from disrupted Wnt signaling resulting in modulation of planar cell polarity (PCP)—a process whereby cells are polarized and aligned. While ciliopathy phenotypes would suggest that cilia are involved in modulating PCP, the mechanistic link between cilia and PCP has been elusive. Our study using a mouse model carrying a mutation in Wdpcp, a gene required for both ciliogenesis and PCP, suggest that Wdpcp modulation of PCP involves interactions with the actin cytoskeleton separate from its function in ciliogenesis. We observe Wdpcp localization in cilia, where it is required for recruitment of proteins essential for ciliogenesis. Wdpcp interacts with Sept2, and is also found in actin filaments, where it regulates actin dynamics essential for PCP. Together, these findings show that PCP regulation by Wdpcp is distinct from its function in ciliogenesis and involves direct modulation of the actin cytoskeleton.
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