Ma Lina, Quigley Ian, Omran Heymut, Kintner Chris
The Salk Institute for Biological Studies, La Jolla 92037, California, USA;
Department of Pediatrics, University Hospital Muenster, 48149 Muenster; Germany.
Genes Dev. 2014 Jul 1;28(13):1461-71. doi: 10.1101/gad.243832.114. Epub 2014 Jun 16.
Multiciliate cells employ hundreds of motile cilia to produce fluid flow, which they nucleate and extend by first assembling hundreds of centrioles. In most cells, entry into the cell cycle allows centrioles to undergo a single round of duplication, but in differentiating multiciliate cells, massive centriole assembly occurs in G0 by a process initiated by a small coiled-coil protein, Multicilin. Here we show that Multicilin acts by forming a ternary complex with E2f4 or E2f5 and Dp1 that binds and activates most of the genes required for centriole biogenesis, while other cell cycle genes remain off. This complex also promotes the deuterosome pathway of centriole biogenesis by activating the expression of deup1 but not its paralog, cep63. Finally, we show that this complex is disabled by mutations in human Multicilin that cause a severe congenital mucociliary clearance disorder due to reduced generation of multiple cilia. By coopting the E2f regulation of cell cycle genes, Multicilin drives massive centriole assembly in epithelial progenitors in a manner required for multiciliate cell differentiation.
多纤毛细胞利用数百根运动性纤毛产生流体流动，它们通过首先组装数百个中心粒来形成并延长这些纤毛。在大多数细胞中，进入细胞周期会使中心粒进行一轮复制，但在分化中的多纤毛细胞中，大量的中心粒组装在G0期通过一种由小的卷曲螺旋蛋白Multicilin启动的过程发生。在这里，我们表明Multicilin通过与E2f4或E2f5以及Dp1形成三元复合物来发挥作用，该复合物结合并激活中心粒生物发生所需的大多数基因，而其他细胞周期基因则保持关闭状态。这种复合物还通过激活deup1而不是其旁系同源物cep63的表达来促进中心粒生物发生的双体途径。最后，我们表明这种复合物因人类Multicilin中的突变而失活，这些突变由于多纤毛生成减少而导致严重的先天性黏液纤毛清除障碍。通过利用细胞周期基因的E2f调控，Multicilin以上皮祖细胞中多纤毛细胞分化所需的方式驱动大量中心粒组装。
