Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York City, New York 10032, USA.
David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.
Nat Commun. 2017 Jul 4;8:15857. doi: 10.1038/ncomms15857.
Abnormal development of multiciliated cells is a hallmark of a variety of human conditions associated with chronic airway diseases, hydrocephalus and infertility. Multiciliogenesis requires both activation of a specialized transcriptional program and assembly of cytoplasmic structures for large-scale centriole amplification that generates basal bodies. It remains unclear, however, what mechanism initiates formation of these multiprotein complexes in epithelial progenitors. Here we show that this is triggered by nucleocytoplasmic translocation of the transcription factor E2f4. After inducing a transcriptional program of centriole biogenesis, E2f4 forms apical cytoplasmic organizing centres for assembly and nucleation of deuterosomes. Using genetically altered mice and E2F4 mutant proteins we demonstrate that centriole amplification is crucially dependent on these organizing centres and that, without cytoplasmic E2f4, deuterosomes are not assembled, halting multiciliogenesis. Thus, E2f4 integrates nuclear and previously unsuspected cytoplasmic events of centriole amplification, providing new perspectives for the understanding of normal ciliogenesis, ciliopathies and cancer.
多纤毛细胞的异常发育是多种人类疾病的标志，这些疾病与慢性气道疾病、脑积水和不育有关。多纤毛发生既需要激活专门的转录程序，又需要组装细胞质结构以进行大规模中心粒扩增，从而产生基底体。然而，目前尚不清楚是什么机制启动了上皮祖细胞中这些多蛋白复合物的形成。在这里，我们表明这是由转录因子 E2f4 的核质易位引发的。在诱导中心体生物发生的转录程序后，E2f4 形成顶细胞质组织中心，用于组装和核化后致密体。使用基因改变的小鼠和 E2F4 突变蛋白，我们证明中心粒扩增严重依赖于这些组织中心，并且，如果没有细胞质中的 E2f4，后致密体就不会组装，多纤毛发生就会停止。因此，E2f4 整合了中心粒扩增的核内和以前未被怀疑的细胞质事件，为理解正常纤毛发生、纤毛病和癌症提供了新的视角。
