Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin.
The muscle actins in higher vertebrates display highly conserved amino acid sequences, yet they show distinct expression patterns. Thus, cardiac alpha-actin, skeletal alpha-actin, vascular smooth muscle alpha-actin, and enteric smooth muscle gamma-actin comprise the major actins in their respective tissues. To assess the functional and developmental significance of cardiac alpha-actin, the murine (129/SvJ) cardiac alpha-actin gene was disrupted by homologous recombination. The majority ( approximately 56%) of the mice lacking cardiac alpha-actin do not survive to term, and the remainder generally die within 2 weeks of birth. Increased expression of vascular smooth muscle and skeletal alpha-actins is observed in the hearts of newborn homozygous mutants and also heterozygotes but apparently is insufficient to maintain myofibrillar integrity in the homozygous mutants. Mice lacking cardiac alpha-actin can be rescued to adulthood by the ectopic expression of enteric smooth muscle gamma-actin using the cardiac alpha-myosin heavy chain promoter. However, the hearts of such rescued cardiac alpha-actin-deficient mice are extremely hypodynamic, considerably enlarged, and hypertrophied. Furthermore, the transgenically expressed enteric smooth muscle gamma-actin reduces cardiac contractility in wild-type and heterozygous mice. These results demonstrate that alterations in actin composition in the fetal and adult heart are associated with severe structural and functional perturbations.
Kumar
A
A
Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Crawford
K
K
Close
L
L
Madison
M
M
Lorenz
J
J
Doetschman
T
T
Pawlowski
S
S
Duffy
J
J
Neumann
J
J
Robbins
J
J
Boivin
G P
GP
O'Toole
B A
BA
Lessard
J L
JL
D000199:Actins / Q000235:genetics*; D000818:Animals; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D006321:Heart / Q000502:physiology*; D006334:Heart Function Tests; D006579:Heterozygote; D006720:Homozygote; D007421:Intestine, Small / Q000737:chemistry; D051379:Mice; D008817:Mice, Mutant Strains; D009130:Muscle, Smooth / Q000737:chemistry; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D011994:Recombinant Proteins / Q000096:biosynthesis; D014018:Tissue Distribution
D000199:Actins; D011994:Recombinant Proteins