Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice

doi:10.1073/pnas.0409103102

Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice

Departments of ^*Molecular Biology and ^†Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, and ^‡Institute of Cell Biology, Department of Molecular Biology, Tuebingen University, D-72704 Tuebingen, Germany

Contributed by Eric N. Olson, December 9, 2004

Abstract

Serum response factor (SRF) controls the transcription of muscle genes by recruiting a variety of partner proteins, including members of the myocardin family of transcriptional coactivators. Mice lacking SRF fail to form mesoderm and die before gastrulation, precluding an analysis of the roles of SRF in muscle tissues. To investigate the functions of SRF in skeletal muscle development, we conditionally deleted the Srf gene in mice by skeletal muscle-specific expression of Cre recombinase. In mice lacking skeletal muscle SRF expression, muscle fibers formed, but failed to undergo hypertrophic growth after birth. Consequently, mutant mice died during the perinatal period from severe skeletal muscle hypoplasia. The myopathic phenotype of these mutant mice resembled that of mice expressing a dominant negative mutant of a myocardin family member in skeletal muscle. These findings reveal an essential role for the partnership of SRF and myocardin-related transcription factors in the control of skeletal muscle growth and maturation in vivo.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: eric.olson{at}utsouthwestern.edu.
Author contributions: C.L. designed research; M.C., J.M., R.B.-D., J.A.R., F.F.W., A.N., and E.N.O. performed research; and E.N.O. wrote the paper.
Abbreviations: MEF2, myocyte enhancer factor 2; SRF, serum response factor; MRTF, myocardin-related transcription factor; dnMRTF-A, dominant negative mutant of MRTF-A; MCK, muscle creatine kinase; H&E, hematoxylin and eosin; E(n), embryonic day n; P(n), postnatal day n.