title: Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene.
abstract: BACKGROUND
  Signals from the extracellular environment control many aspects of cell behaviour including proliferation, survival, differentiation, adhesion and migration. It is increasingly evident that these signals can be modulated by a group of matricellular proteins called the CCN family. CCN proteins have multiple domains through which they regulate the activities of a variety of signalling molecules including TGFbeta, BMPs and integrins, thereby influencing a wide range of processes in development and disease. Whilst the developmental roles of CCN1 and CCN2 have been elucidated, very little is known about the function of CCN3 (NOV). To investigate this, we have generated mice carrying a targeted mutation in the Nov gene (Novdel3) which reveal for the first time its diverse functions in embryos and adults.
  
  
  RESULTS
  By replacing Nov exon 3 with a TKneomycin cassette, we have generated Novdel3-/- mice which produce no full length NOV protein and express at a barely detectable level a mutant NOV protein that lacks the VWC domain. In Novdel3-/- embryos, and to a lesser extent in Novdel3+/- embryos, development of the appendicular and axial skeleton was affected with enlarged vertebrae, elongated long bones and digits, delayed ossification, increased bone mineralization and severe joint malformations. Primary embryo fibroblasts from Novdel3-/- mutant embryos showed enhanced chondrogenesis and osteogenesis. Cardiac development was also influenced leading to enlargement and abnormal modelling of the endocardial cushions, associated with septal defects and delayed fusion. In adults, cardiomyopathy was apparent, with hypertrophy and calcification of the septum and left ventricle dilation. Muscle atrophy was seen by 5 months of age, associated with transdifferentiation to fat. Premature tissue degeneration was also seen in the lens, with cataracts present from 6 months.
  
  
  CONCLUSIONS
  We have generated the first mice with a mutation in the Nov gene (Novdel3). Our data demonstrate that NOV is a regulator of skeletal and cardiac development, and implicates NOV in various disease processes including cardiomyopathy, muscle atrophy and cataract formation. Novdel3 mutants represent a valuable resource for studying NOV's role in the modulation and co-ordination of multiple signalling pathways that underpin organogenesis and tissue homeostasis.
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. e.heath@gen.cam.ac.uk
authors.forename: Emma
authors.initials: E
authors.lastname: Heath
authors.forename: Dalal
authors.initials: D
authors.lastname: Tahri
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Andermarcher
authors.forename: Paul
authors.initials: P
authors.lastname: Schofield
authors.forename: Stewart
authors.initials: S
authors.lastname: Fleming
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Boulter
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000196:embryology; D002114:Calcinosis / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics*; D002386:Cataract / Q000235:genetics*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000473:pathology; D020219:Chondrogenesis; D055513:Connective Tissue Growth Factor; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006321:Heart / Q000196:embryology*; D006579:Heterozygote; D006720:Homozygote; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009133:Muscular Atrophy / Q000235:genetics*; D050505:Mutant Proteins / Q000378:metabolism; D055514:Nephroblastoma Overexpressed Protein; D010012:Osteogenesis
chemical_list: C526318:CCN2 protein, mouse; C526320:Ccn3 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D055514:Nephroblastoma Overexpressed Protein; D055513:Connective Tissue Growth Factor