Development of a smooth muscle-targeted cre recombinase mouse reveals novel insights regarding smooth muscle myosin heavy chain promoter regulation

The use of genetically modified mice has been an important model system to study gene function in cardiovascular development and under pathophysiologi cal conditions. Although conventional gene knockout studies have provided i mportant insights into gene function in the cardiovascular system, they may be limited by upregulation of compensatory pathways and the inability to d ifferentiate direct versus indirect functions in vivo. As a first step in d eveloping systems that can target gene activation or inactivation specifica lly to smooth muscle cells (SMCs), we coupled the smooth muscle myosin heav y chain (SMMHC) promoter to the cre recombinase gene and generated transgen ic mice that express cre in SMCs. In addition, we used these mice to addres s whether the heterogeneous staining observed in SMMHC-LacZ mice was due to subsets of SMCs that required different regulatory cassettes of the promot er or if it reflected episodic expression of the transgene. To address both the feasibility of SMC targeting and the apparent heterogeneous expression , we bred SMMHC-cre mice to indicator mice containing a cre-activated LacZ gene. Results showed high-level expression in SMCs at various embryonic tim e points and in adult tissues. Because breeding of SMMHC-cre mice to an ind icator line provided an integration of cre activity over time, results of t his study revealed that expression of the SMMHC promoter fragment more clos ely resembled the expression of the endogenous gene, both with respect to t he onset of activation during development and uniformity of staining among individual cells within tissues. Overall, these mice will provide a powerfu l tool to researchers to study gene function in vascular-development/diseas e by using cre/lox technology to direct smooth muscle-specific gene activat ion or inactivation in vivo.