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

• Published in: The EMBO journal 2015-04, Vol.34 (8), p.1078-1089
• Main Authors: Funk, Maja C, Bera, Agata N, Menchen, Tabea, Kuales, Georg, Thriene, Kerstin, Lienkamp, Soeren S, Dengjel, Jörn, Omran, Heymut, Frank, Marcus, Arnold, Sebastian J
• Format: Article
• Language: English
• Subjects: Animals; Ccno; Cell Differentiation - genetics; Cells, Cultured; Cellular biology; centriole amplification; Centrioles - physiology; Centrioles - ultrastructure; Cilia - physiology; Cilia - ultrastructure; Cyclins - physiology; Cystic fibrosis; deuterosomes; EMBO05; EMBO11; EMBO24; Embryo, Mammalian; Gene Expression Regulation, Developmental; Genotype & phenotype; Hydrocephalus - embryology; Hydrocephalus - genetics; Mice; Mice, Transgenic; mouse; Mucociliary Clearance - genetics; multiciliated cells; Mutation; Organogenesis - genetics; Trachea - cytology; Trachea - embryology; Trachea - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201490805

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. Synopsis Cyclin O mutations cause congenital mucociliary clearance disorder linked to a reduced number of motile cilia in the airway epithelium. This is caused by malfunctioning deuterosomes that lead to fewer and partially defective centrioles. Ccno is expressed early in the embryonic node, and in respiratory and ependymal multiciliated cells (MCCs) later on. MCCs lacking Ccno generate fewer centrioles that often fail to dock to the plasma membrane, resulting in fewer motile cilia. Deuterosomes of Ccno ‐deficient MCCs are enlarged in size, reduced in number and functionally compromised. These deuterosomes generate fewer and partially non‐functional centrioles. Graphical Abstract Cyclin O mutations cause congenital mucociliary clearance disorder linked to a reduced number of motile cilia in the airway epithelium. This is caused by malfunctioning deuterosomes that lead to fewer and partially defective centrioles.