Constitutive Cyclin O deficiency results in penetrant hydrocephalus, impaired growth and infertility

// Marc Nunez-Olle 1 , Carole Jung 2 , Berta Terre 3 , Norman A. Balsiger 1 , Cristina Plata 2 , Ramon Roset 1 , Carlos Pardo-Pastor 2 , Marta Garrido 1 , Santiago Rojas 4 , Francesc Alameda 1,5 , Josep Lloreta 5 , Juan Martin-Caballero 6 , Juana M. Flores 7 , Travis H. Stracker 3 , Miguel A. Valverde 2 , Francisco J. Munoz 2,* and Gabriel Gil-Gomez 1,* 1 Apoptosis Signalling Group, IMIM (Institut Hospital del Mar d’Investigacions Mediques), Barcelona, Spain 2 Laboratory of Molecular Physiology, Universitat Pompeu Fabra, Barcelona, Spain 3 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain 4 Unit of Human Anatomy and Embryology, Department of Morphological Science, Faculty of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Spain 5 Servei de Patologia, Hospital del Mar-IMIM (Institut Hospital del Mar d’Investigacions Mediques), Barcelona, Spain 6 Parc de Recerca Biomedica de Barcelona, Barcelona, Spain 7 Departamento de Medicina y Cirugia Animal, Facultad Veterinaria, Universidad Complutense de Madrid, Madrid, Spain * Co-corresponding authors Correspondence to: Gabriel Gil-Gomez, email: // Francisco J. Munoz, email: // Keywords : Cyclin O, ciliogenesis, neurogenesis, hydrocephalus, development, Gerotarget Received : May 04, 2017 Accepted : October 02, 2017 Published : October 12, 2017 Abstract Cyclin O (encoded by CCNO ) is a member of the cyclin family with regulatory functions in ciliogenesis and apoptosis. Homozygous CCNO mutations have been identified in human patients with Reduced Generation of Multiple Motile Cilia (RGMC) and conditional inactivation of Ccno in the mouse recapitulates some of the pathologies associated with the human disease. These include defects in the development of motile cilia and hydrocephalus. To further investigate the functions of Ccno in vivo , we have generated a new mouse model characterized by the constitutive loss of Ccno in all tissues and followed a cohort during ageing. Ccno -/- mice were growth impaired and developed hydrocephalus with high penetrance. In addition, some Ccno +/- mice also developed hydrocephalus and affected Ccno -/- and Ccno +/- mice exhibited additional CNS defects including cortical thinning and hippocampal abnormalities. In addition to the CNS defects, both male and female Ccno -/- mice were infertile and female mice exhibited few motile cilia in the oviduct. Our results further establish CCNO as an important gene for normal development and suggest that heterozygous CCNO mutations could underlie hydrocephalus or diminished fertility in some human patients.