MOLECULAR AND PHYSIOLOGICAL-EFFECTS OF ALPHA-TROPOMYOSIN ABLATION IN THE MOUSE

Tropomyosin (TM) is an integral component of the thin filament in musc le fibers and is involved in regulating actin-myosin interactions. TM is encoded by a family of four alternatively spliced genes that displa y highly conserved nucleotide and amino acid sequences. To assess the functional and developmental significance of alpha-TM, the murine alph a-TM gene was disrupted by homologous recombination. Homozygous alpha- TM null mice are embryonic lethal, dying between 8 and 11.5 days post coitum. Mice that are heterozygous for alpha-TM are viable and reprodu ce normally. Heterozygous knockout mouse hearts show a 50% reduction i n cardiac muscle alpha-TM mRNA, with no compensatory increase in trans cript levels by striated muscle beta-TM or TM-30 isoforms. Surprisingl y, this reduction in alpha-TM mRNA levels in heterozygous mice is not reflected at the protein level, where normal amounts of striated muscl e alpha-TM protein are produced and integrated in the myofibril, Quant ification of alpha-TM mRNA bound in polysomal fractions reveals that b oth wild-type and heterozygous knockout animals have similar levels. T hese data suggest that a change in steady-state level of alpha-TM mRNA does not affect the relative amount of mRNA translated and amount of protein synthesized. Physiological analyses of myocardial and myofilam ent function show no differences between heterozygous alpha-TM mice an d control mice. The present study suggests that translational regulati on plays a major role in the control of TM expression.