DEVELOPMENTAL AND TISSUE-SPECIFIC REGULATION OF THE MURINE CARDIAC ACTIN GENE IN-VIVO DEPENDS ON DISTINCT SKELETAL AND CARDIAC MUSCLE-SPECIFIC ENHANCER ELEMENTS IN ADDITION TO THE PROXIMAL PROMOTER

Cardiac actin is an early marker of cardiac and skeletal muscle lineag es in the mouse. After birth, the gene is downregulated in skeletal mu scle. High-level expression of the murine cardiac actin gene in skelet al myotubes in vitro involves distal(-7.8/-7.0 kb) and proximal(-5.4/- 3.5 kb) enhancer sequences as well as the proximal promoter (-0.7/+0.1 kb). Transgenic mice carrying an nlacZ reporter gene under the contro l of different fragments of the upstream region of the cardiac actin g ene were generated. This analysis led to the conclusions that (1) the proximal promoter is a weak but tissue specific element in vivo, (2) c onsistent high-level expression in skeletal muscle depends on the pres ence of at least one of the enhancers, (3) expression in adult cardiac muscle requires a cardiac enhancer located in the (-5.4/-0.7 kb) regi on, and (4) a construct containing these three elements gives a strong specific expression of the transgene in the heart throughout the life of the animal and in embryonic skeletal muscle. All transgenes tested reproduce the down-regulation observed in adult skeletal muscle for t he cardiac actin gene. Nonuniform expression of these transgenes in th e heart may mark cardiomyocytes derived from different cardiac progeni tors. (C) 1996 Academic Press, Inc.