Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Commun Biol. 2024 Nov 4;7(1):1430. doi: 10.1038/s42003-024-07150-0.
Motile cilia are critical structures that regulate early embryonic development and tissue homeostasis through synchronized ciliary motility. The formation of motile cilia is dependent on precisely controlled sequential processes including the generation, migration, and docking of centrioles/basal bodies as well as ciliary growth. Using the published proteomics data from various organisms, we identified proliferation-associated 2G4 as a novel regulator of ciliogenesis. Loss-of-function studies using Xenopus laevis as a model system reveal that Pa2G4 is essential for proper ciliogenesis and synchronized movement of cilia in multiciliated cells (MCCs) and the gastrocoel roof plate (GRP). Pa2G4 morphant MCCs exhibit defective basal body docking to the surface as a result of compromised Rac1 activity, apical actin network formation, and immature distal appendage generation. Interestingly, the regions that include the RNA-binding domain and the C-terminus of Pa2G4 are necessary for ciliogenesis in both MCCs and GRP cells. Our findings may provide insights into motile cilia-related genetic diseases such as Primary Ciliary Dyskinesia.
纤毛是重要的结构，通过同步纤毛运动调节早期胚胎发育和组织动态平衡。纤毛的形成依赖于精确控制的顺序过程，包括中心粒/基体的产生、迁移和对接以及纤毛的生长。利用来自各种生物体的已发表的蛋白质组学数据，我们鉴定出增殖相关蛋白 2G4 是纤毛发生的新型调节因子。利用非洲爪蟾作为模型系统的功能丧失研究表明，Pa2G4 对于多纤毛细胞 (MCC) 和胃腔顶板 (GRP) 中正确的纤毛发生和纤毛的同步运动是必需的。由于 Rac1 活性受损、顶 actin 网络形成和不成熟的远端附属物生成，Pa2G4 突变体 MCC 中的基底体与表面的对接存在缺陷。有趣的是，包括 RNA 结合域和 Pa2G4 C 末端的区域对于 MCC 和 GRP 细胞中的纤毛发生都是必需的。我们的发现可能为纤毛相关的遗传疾病，如原发性纤毛运动障碍，提供一些见解。
