A viral FLIP protein, E8, exogenously-expressed in the mesenchymal lineage of mice leads to bone malformations, lipoatrophy, and muscular atrophy

Abstract

The equine herpes virus 2, E8 protein is a member of the viral FLIP family, and as such, it is a potent inhibitor of death receptor-induced apoptosis in cultured cells. To extend our study of the effects of E8 to animals, we generated a mouse model in which the progeny of a cross between two transgenic mice conditionally express E8 under the control of the collagen type I α2 chain (Col1α2) promoter, allowing us to monitor and characterize the effects of E8 expression in the mesenchymal cell lineage. We observed growth defects associated with irregular bone formation during development. In addition, adult animals exhibited both lipoatrophy-like and muscular atrophy-like symptoms. These abnormal phenotypes likely arise from incomplete differentiation of mesenchymal stem cells (MSCs). To examine this hypothesis in more detail, we expressed E8 in the mouse MSC line C3H10T1/2 and performed a microarray analysis. Factors such as Nov/CCN3, STEAP4, and Ankrd1/CARP, which are involved in differentiation from MSCs to osteoblasts, adipocytes and myoblasts were affected. Taken together, our results demonstrate that the constitutive expression of herpesvirus gene products in the mesenchymal progenitors affects differentiation into multiple cell lineages.