Abstract
BackgroundSignals 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 TGFβ, 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.ResultsBy 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.ConclusionWe 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.
Highlights
Signals from the extracellular environment control many aspects of cell behaviour including proliferation, survival, differentiation, adhesion and migration
The carboxy- terminal (CT) domain of CTGF has been shown to interact with the Wnt co-receptor lowdensity lipoprotein (LDL) receptor-related protein 6 (LRP6), thereby inhibiting Wnt signalling [14]; a similar domain is present in another novel modulator of Wnt signalling, WISE [15] and modulation of Wnt signalling through this domain has been demonstrated for Cyr61 [16]
Both the wild type and targeted Nov alleles were expressed in primary embryonic fibroblasts (PEFs) derived respectively from wild type and Novdel3-/- E13.5 embryos
Summary
Signals from the extracellular environment control many aspects of cell behaviour including proliferation, survival, differentiation, adhesion and migration. There is increasing evidence that a family of matricellular proteins, the CCN family, is a central player in regulating several of these signalling molecules (reviewed in [1]) By modulating their activities, CCN family members profoundly influence the behaviour of cells in development, wound healing, tissue homeostasis and in a range of diseases, including fibrosis and cancer. Their diverse effects are mediated by four cysteine-rich conserved domains which are shared by all members of the family, with the exception of WISP2 which lacks the C-terminal domain [2] Through these domains, CCN proteins interact with a variety of extra-cellular signalling molecules, thereby regulating and potentially co-ordinating their activities. Many of the effects of different CCN family members involve signalling through a variety of integrins which interact with different domains in the CCN proteins [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
