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 lea...

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Bibliographic Details
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
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
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Summary: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. 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.
ISSN:0261-4189
1460-2075
DOI:10.15252/embj.201490805