Cyclin O (Ccno) functions during deuterosome‐mediated centriole amplification of multiciliated cells

Mucociliary clearance and fluid transport along epithelial surfaces are carried out by multiciliated cells (MCCs). Recently, human mutations in Cyclin O (CCNO) were linked to severe airway disease. Here, we show that Ccno expression is restricted to MCCs and the genetic deletion of Ccno in mouse leads to reduced numbers of multiple motile cilia and characteristic phenotypes of MCC dysfunction including severe hydrocephalus and mucociliary clearance deficits. Reduced cilia numbers are caused by compromised generation of centrioles at deuterosomes, which serve as major amplification platform for centrioles in MCCs. Ccno‐deficient MCCs fail to sufficiently generate deuterosomes, and only reduced numbers of fully functional centrioles that undergo maturation to ciliary basal bodies are formed. Collectively, this study implicates CCNO as first known regulator of deuterosome formation and function for the amplification of centrioles in MCCs.

[1]  H. Omran,et al.  When cilia go bad: cilia defects and ciliopathies , 2008, Nature Reviews Molecular Cell Biology.

[2]  H. Omran,et al.  Multicilin drives centriole biogenesis via E2f proteins , 2014, Genes & development.

[3]  J. Harrow,et al.  A conditional knockout resource for the genome-wide study of mouse gene function , 2011, Nature.

[4]  Erich A. Nigg,et al.  Cep164, a novel centriole appendage protein required for primary cilium formation , 2007, The Journal of cell biology.

[5]  A. McMahon,et al.  Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain , 2002, Mechanisms of Development.

[6]  Xiumin Yan,et al.  The Cep63 paralogue Deup1 enables massive de novo centriole biogenesis for vertebrate multiciliogenesis , 2013, Nature Cell Biology.

[7]  Lance Lee.  Riding the wave of ependymal cilia: Genetic susceptibility to hydrocephalus in primary ciliary dyskinesia , 2013, Journal of neuroscience research.

[8]  M. Werner,et al.  Deuterosome-mediated centriole biogenesis. , 2013, Developmental cell.

[9]  Nathalie Spassky,et al.  Centriole amplification by mother and daughter centrioles differs in multiciliated cells , 2014, Nature.

[10]  T. Tang.  Centriole biogenesis in multiciliated cells , 2013, Nature Cell Biology.

[11]  H. Hamada,et al.  The left-right axis in the mouse: from origin to morphology , 2006, Development.

[12]  S. Sorokin.  Reconstructions of centriole formation and ciliogenesis in mammalian lungs. , 1968, Journal of cell science.

[13]  J. Raff,et al.  Centrioles, Centrosomes, and Cilia in Health and Disease , 2009, Cell.

[14]  Lin He,et al.  miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110 , 2014, Nature.

[15]  L. A. Daniels,et al.  Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. , 2013, American journal of respiratory and critical care medicine.

[16]  H. Omran,et al.  Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia. , 2005, American journal of respiratory and critical care medicine.

[17]  B. Hogan,et al.  Lung development and repair: Contribution of the ciliated lineage , 2007, Proceedings of the National Academy of Sciences.

[18]  D. Nicastro,et al.  Drosophila asterless and Vertebrate Cep152 Are Orthologs Essential for Centriole Duplication , 2008, Genetics.

[19]  A. Spektor,et al.  Cep97 and CP110 Suppress a Cilia Assembly Program , 2007, Cell.

[20]  T. Stearns,et al.  Molecular characterization of centriole assembly in ciliated epithelial cells , 2007, The Journal of cell biology.

[21]  S. Brody,et al.  Analysis of ciliogenesis in primary culture mouse tracheal epithelial cells. , 2013, Methods in enzymology.

[22]  B. Durand,et al.  Two rotating cilia in the node cavity are sufficient to break left–right symmetry in the mouse embryo , 2012, Nature Communications.

[23]  Sebastian A. Leidel,et al.  Regulated HsSAS-6 levels ensure formation of a single procentriole per centriole during the centrosome duplication cycle. , 2007, Developmental cell.

[24]  S. Shapiro,et al.  Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice. , 2000, American journal of respiratory cell and molecular biology.

[25]  H. Omran,et al.  Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia , 2014, Nature Genetics.

[26]  E. Nigg,et al.  Plk4-induced centriole biogenesis in human cells. , 2007, Developmental cell.

[27]  J. Chen,et al.  Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. , 1998, The Journal of clinical investigation.

[28]  M. Knowles,et al.  Primary ciliary dyskinesia , 2012 .

[29]  S. Brody,et al.  Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. , 2002, American journal of physiology. Lung cellular and molecular physiology.