Animal models represent an invaluable tool, which must be judiciously used to provide the greatest benefit to human kind, due to their cost and time effectiveness. The CCN2 null mouse model described in this paper represents a new murine model of craniofacial development. This model is notable for its remarkably consistent phenotype and ease of colony care and propagation. The interaction of CCN2 with the TGF-β, BMP, FGF, EGF, Integrin, and WNT proteins is currently under investigated and signifies a plethora of research opportunities that may help elucidate novel therapeutic options for future patients. This paper presents a descriptive overview of the known craniofacial developmental abnormalities of this model as well as the known molecular signaling aberrances that provide clues to direct future investigative endeavors.
BrigstockDRGoldschmedingRKatsubeKI, et al. Proposal for a unified CCN nomenclature. Mol Pathol. 2003;56(2):127-128.
2.
ArnottJALambiAGMundyC, et al. The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis. Crit Rev Eukaryotic Gene Express. 2011;21(1):43-69.
3.
Rayego-MateosSRodrigues-DíezRMorgado-PascualJL, et al. Connective tissue growth factor is a new ligand of epidermal growth factor receptor. J Mol Cell Biol. 2013;5(5):323-335.
ButlerGSConnorARSounniNE, et al. Degradomic and yeast 2-hybrid inactive catalytic domain substrate trapping identifies new membrane-type 1 matrix metalloproteinase (MMP14) substrates: CCN3 (Nov) and CCN5 (WISP2). Matrix Biol. 2017;59:23-38.
6.
GaoRBrigstockDR.Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin Alpha(v)beta(3) and heparan sulfate proteoglycan. J Biol Chem. 2004;279(10):8848-8855.
7.
BradhamDMIgarashiAPotterRLGrotendorstGR.Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol. 1991;114(6):1285-1294.
8.
HendesiHBarbeMFSafadiFFMonroyMAPopoffSN.Integrin mediated adhesion of osteoblasts to connective tissue growth factor (CTGF/CCN2) induces cytoskeleton reorganization and cell differentiation. PLoS One. 2015;10(2):e0115325.
9.
AbreuJGKetpuraNIReversadeBDe RobertisEM.Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol. 2002;4(8):599-604.
NishidaTKawakiHBaxterRMDeyoungRATakigawaMLyonsKM.CCN2 (connective tissue growth factor) is essential for extracellular matrix production and integrin signaling in chondrocytes. J Cell Commun Signaling. 2007;1(1):45-58.
12.
NishidaTKubotaSAoyamaEJanuneDMaedaATakigawaM.Effect of CCN2 on FGF2-induced proliferation and MMP9 and MMP13 productions by chondrocytes. Endocrinology. 2011;152(11):4232-4241.
13.
AbdElKaderTKubotaSAnnoK, et al. Direct interaction between CCN family protein 2 and fibroblast growth factor 1. J Cell Commun Signaling. 2014;8(2):157-163.
14.
AoyamaEHattoriTHoshijimaM, et al. N-terminal domains of CCN family 2/connective tissue growth factor bind to aggrecan. Biochem J. 2009;420(3):413-420.
15.
TarrJTLambiAGBradleyJPBarbeMFPopoffSN.Development of normal and cleft palate: a central role for connective tissue growth factor (CTGF/CCN2). J Dev Biol. 2018;6(3):18.
16.
BrigstockDR.The CCN family: a new stimulus package. J Endocrinol. 2003;178(2):169-175.
17.
LambiAGPankratzTLMundyC, et al. The skeletal site-specific role of connective tissue growth factor in prenatal osteogenesis. Dev Dyn. 2012;241(12):1944-1959.
18.
IvkovicSYoonBSPopoffSN, et al. Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development. 2003;130(12):2779-2791.
19.
BattulaVLChenYCabreira MdaG, et al. Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood. 2013;122(3):357-366.
20.
WellsJEHowlettMColeCHKeesUR.Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer. Int J Cancer. 2015;137:504-511.
21.
BrigstockDR.Strategies for blocking the fibrogenic actions of connective tissue growth factor (CCN2): from pharmacological inhibition in vitro to targeted siRNA therapy in vivo. J Cell Commun Signaling. 2009;3(1):5-18.
22.
BrigstockDR.Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals. J Cell Commun Signaling. 2010;4(1):1-4.
23.
TsaiHCSuHLHuangCYFongYCHsuCJTangCH.CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d. Oncotarget. 2014;5(11):3800-3812.
24.
TsaiHCHuangCYSuHLTangCH.CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma. PLoS One. 2014;9(3):e90159.
25.
MaoZMaXRongY, et al. Connective tissue growth factor enhances the migration of gastric cancer through downregulation of E-cadherin via the NF-κB pathway. Cancer Sci. 2011;102(1):104-110.
26.
XiuMLiuYHBrigstockDRHeFHZhangRJGaoRP.Connective tissue growth factor is overexpressed in human hepatocellular carcinoma and promotes cell invasion and growth. World J Gastroenterol. 2012;18(47):7070-7078.
27.
CrawfordLAGuneyMAOhYA, et al. Connective tissue growth factor (CTGF) inactivation leads to defects in islet cell lineage allocation and beta-cell proliferation during embryogenesis. Mol Endocrinol. 2009;23(3):324-336.
28.
TarrJTVisserTGMoonJE, et al. The pivotal role of CCN2 in mammalian palatogenesis. J Cell Commun Signaling. 2017;11(1):25-37.
29.
ArnottJAZhangXSanjayA, et al. Molecular requirements for induction of CTGF expression by TGF-beta1 in primary osteoblasts. Bone. 2008;42(5):871-885.
30.
EconomidesANFrendeweyDYangP, et al. Conditionals by inversion provide a universal method for the generation of conditional alleles. Proc Natl Acad Sci USA. 2013;110(34):E3179-E3188.
