Restricted inactivation of serum response factor to the cardiovascular system

Joseph M. Miano, Narendrakumar Ramanan, Mary A. Georger, Karen L. De Mesy Bentley, Rachael L. Emerson, Robert O. Balza, Qi Xiao, Hartmut Weiler, David D. Ginty, Ravi P. Misra

Research output: Contribution to journalArticle

Abstract

Serum response factor (SRF) directs programs of gene expression linked to growth and muscle differentiation. To investigate the role of SRF in cardiovascular development, we generated mice in which SRF is knocked out in >80% of cardiomyocytes and >50% of vascular smooth muscle cells (SMC) through SM22α-Cre-mediated excision of SRF's promoter and first exon. Mutant mice display vascular patterning, cardiac looping, and SRF-dependent gene expression through embryonic day (e)9.5. At e10.5, attenuation in cardiac trabeculation and compact layer expansion is noted, with an attendant decrease in vascular SMC recruitment to the dorsal aorta. Ultrastructurally, cardiac sarcomeres and Z disks are highly disorganized in mutant embryos. Moreover, SRF mutant mice exhibit vascular SMC lacking organizing actin/intermediate filament bundles. These structural defects in the heart and vasculature coincide with decreases in SRF-dependent gene expression, such that by e11.5, when mutant embryos succumb to death, no SRF-dependent mRNA expression is evident. These results suggest a vital role for SRF in contractile/cytoskeletal architecture necessary for the proper assembly and function of cardiomyocytes and vascular SMC.

Original languageEnglish (US)
Pages (from-to)17132-17137
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number49
DOIs
StatePublished - Dec 7 2004

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Keywords

  • Cre recombinase
  • Knockout
  • Myocardin
  • SM22α

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Miano, J. M., Ramanan, N., Georger, M. A., De Mesy Bentley, K. L., Emerson, R. L., Balza, R. O., Xiao, Q., Weiler, H., Ginty, D. D., & Misra, R. P. (2004). Restricted inactivation of serum response factor to the cardiovascular system. Proceedings of the National Academy of Sciences of the United States of America, 101(49), 17132-17137. https://doi.org/10.1073/pnas.0406041101