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

163 Citations (Scopus)

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
StatePublished - 1997
Externally publishedYes

Fingerprint

Smooth Muscle
Actins
Vascular Smooth Muscle
Cardiac Myosins
Fetal Heart
Myosin Heavy Chains
Homologous Recombination
Heterozygote
Vertebrates
Amino Acid Sequence
Parturition

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ- actin. / Kumar, A.; Crawford, K.; Close, L.; Madison, M.; Lorenz, J.; Doetschman, Thomas C; Pawlowski, S.; Duffy, J.; Neumann, J.; Robbins, J.; Boivin, G. P.; O'Toole, B. A.; Lessard, J. L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 9, 1997, p. 4406-4411.

Research output: Contribution to journalArticle

Kumar, A, Crawford, K, Close, L, Madison, M, Lorenz, J, Doetschman, TC, Pawlowski, S, Duffy, J, Neumann, J, Robbins, J, Boivin, GP, O'Toole, BA & Lessard, JL 1997, 'Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ- actin', Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4406-4411. https://doi.org/10.1073/pnas.94.9.4406
Kumar, A. ; Crawford, K. ; Close, L. ; Madison, M. ; Lorenz, J. ; Doetschman, Thomas C ; Pawlowski, S. ; Duffy, J. ; Neumann, J. ; Robbins, J. ; Boivin, G. P. ; O'Toole, B. A. ; Lessard, J. L. / Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ- actin. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 9. pp. 4406-4411.
@article{a117dcaaab474e688e2acd9fc137a993,
title = "Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ- actin",
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.",
author = "A. Kumar and K. Crawford and L. Close and M. Madison and J. Lorenz and Doetschman, {Thomas C} and S. Pawlowski and J. Duffy and J. Neumann and J. Robbins and Boivin, {G. P.} and O'Toole, {B. A.} and Lessard, {J. L.}",
year = "1997",
doi = "10.1073/pnas.94.9.4406",
language = "English (US)",
volume = "94",
pages = "4406--4411",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "9",

}

TY - JOUR

T1 - Rescue of cardiac α-actin-deficient mice by enteric smooth muscle γ- actin

AU - Kumar, A.

AU - Crawford, K.

AU - Close, L.

AU - Madison, M.

AU - Lorenz, J.

AU - Doetschman, Thomas C

AU - Pawlowski, S.

AU - Duffy, J.

AU - Neumann, J.

AU - Robbins, J.

AU - Boivin, G. P.

AU - O'Toole, B. A.

AU - Lessard, J. L.

PY - 1997

Y1 - 1997

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0031001970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031001970&partnerID=8YFLogxK

U2 - 10.1073/pnas.94.9.4406

DO - 10.1073/pnas.94.9.4406

M3 - Article

C2 - 9114002

AN - SCOPUS:0031001970

VL - 94

SP - 4406

EP - 4411

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -