Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ- actin

A. Kumar, K. Crawford, L. Close, M. Madison, J. Lorenz, Thomas C Doetschman, S. Pawlowski, J. Duffy, J. Neumann, J. Robbins, G. P. Boivin, B. A. O'Toole, J. L. Lessard

Research output: Contribution to journalArticle

166 Scopus citations

Abstract

The muscle actins in higher vertebrates display highly conserved amino acid sequences, yet they show distinct expression patterns. Thus, cardiac α- actin, skeletal α-actin, vascular smooth muscle α-actin, and enteric smooth muscle γ-actin comprise the major actins in their respective tissues. To assess the functional and developmental significance of cardiac α-actin, the murine (129/SvJ) cardiac α-actin gene was disrupted by homologous recombination. The majority (≃56%) of the mice lacking cardiac α-actin do not survive to term, and the remainder generally die within 2 weeks of birth. Increased expression of vascular smooth muscle and skeletal α-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 α-actin can be rescued to adulthood by the ectopic expression of enteric smooth muscle γ-actin using the cardiac α-myosin heavy chain promoter. However, the hearts of such rescued cardiac α-actin-deficient mice are extremely hypodynamic, considerably enlarged, and hypertrophied. Furthermore, the transgenically expressed enteric smooth muscle γ-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.

Original languageEnglish (US)
Pages (from-to)4406-4411
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number9
DOIs
Publication statusPublished - 1997
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • General

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