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Promoter Function of the Angiogenic Inducer Cyr61Gene in Transgenic Mice: Tissue Specificity, Inducibility During Wound Healing, and Role of the Serum Response Element¹

Branko V. Latinki², Fan-E Mo, Jeffrey A. Greenspan, Neal G. Copeland, Debra J. Gilbert, Nancy A. Jenkins, Susan R. Ross and Lester F. Lau

Department of Molecular Genetics (B.V.L., F.-E.M., L.F.L.), University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607-7170; Munin Corporation (J.A.G.), Chicago, Illinois 60612; Mouse Cancer Genetics Program (N.G.C., D.J.G., N.A.J.), National Cancer Institute-Frederick, Frederick, Maryland 21702; and Department of Microbiology (S.R.R.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6142

Address all correspondence and requests for reprints to: Lester F. Lau, Ph.D., Department of Molecular Genetics, University of Illinois at Chicago College of Medicine, 900 South Ashland Avenue, Chicago, Illinois 60607-7170. E-mail: lflau{at}uic.edu

The cysteine-rich angiogenic protein 61 (Cyr61) is an extracellular matrix-associated, heparin-binding protein that mediates cell adhesion, stimulates cell migration, and enhances growth factor-induced cell proliferation. Cyr61 also promotes chondrogenic differentiation and induces neovascularization. In this study, we show that a 2-kb fragment of the Cyr61 promoter, which confers growth factor-inducible expression in cultured fibroblasts, is able to drive accurate expression of the reporter gene lacZ in transgenic mice. Thus, transgene expression was observed in the developing placenta and embryonic cardiovascular, skeletal, and central and peripheral nervous systems. The sites of transgene expression are consistent with those observed of the endogenous Cyr61 gene as determined by in situ hybridization and immunohistochemistry. The transgene expression in the cardiovascular system does not require the serum response element, a promoter sequence essential for transcriptional activation of Cyr61 by serum growth factors in cultured fibroblasts. Because the serum response element contains the CArG box, a sequence element implicated in cardiovascular-specific gene expression, the nonessential nature of this sequence for cardiovascular expression of Cyr61 is unexpected. Furthermore, the Cyr61 promoter-driven lacZ expression is inducible in granulation tissue during wound healing, as is synthesis of the endogenous Cyr61 protein, suggesting a role for Cyr61 in wound healing. Consistent with this finding, purified Cyr61 protein promotes the healing of a wounded fibroblast monolayer in culture. In addition, we mapped the mouse Cyr61 gene to the distal region of chromosome 3. Together, these results define the functional Cyr61 promoter in vivo, and suggest a role of Cyr61 in wound healing through its demonstrated angiogenic activities upon endothelial cells and its chemotactic and growth promoting activities upon fibroblasts.