Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis

Munemasa Mori, Renin Hazan, Paul S. Danielian, John E. Mahoney, Huijun Li, Jining Lu, Emily S. Miller, Xueliang Zhu, Jacqueline A. Lees and Wellington V. Cardoso
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Munemasa Mori: Columbia Center for Human Development, Pulmonary Allergy Critical Care, Columbia University Medical Center
Renin Hazan: David H. Koch Institute for Integrative Cancer Research, MIT
Paul S. Danielian: David H. Koch Institute for Integrative Cancer Research, MIT
John E. Mahoney: Columbia Center for Human Development, Pulmonary Allergy Critical Care, Columbia University Medical Center
Huijun Li: Columbia Center for Human Development, Pulmonary Allergy Critical Care, Columbia University Medical Center
Jining Lu: Columbia Center for Human Development, Pulmonary Allergy Critical Care, Columbia University Medical Center
Emily S. Miller: David H. Koch Institute for Integrative Cancer Research, MIT
Xueliang Zhu: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Jacqueline A. Lees: David H. Koch Institute for Integrative Cancer Research, MIT
Wellington V. Cardoso: Columbia Center for Human Development, Pulmonary Allergy Critical Care, Columbia University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15857

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