Faculty Collaboration Database

Restricted inactivation of serum response factor to the cardiovascular system. Proc Natl Acad Sci U S A 2004 Dec 07;101(49):17132-7

Date

12/01/2004

Pubmed ID

15569937

Pubmed Central ID

PMC535359

DOI

10.1073/pnas.0406041101

Scopus ID

2-s2.0-10344236515 (requires institutional sign-in at Scopus site)   211 Citations

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 SM22alpha-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.

Author List

Miano JM, Ramanan N, Georger MA, de Mesy Bentley KL, Emerson RL, Balza RO Jr, Xiao Q, Weiler H, Ginty DD, Misra RP

Authors

Ravindra P. Misra PhD Associate Provost, Professor in the Biochemistry department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cardiovascular Abnormalities
Cardiovascular System
Embryo, Mammalian
Fetal Growth Retardation
Gene Expression Regulation
Heart Defects, Congenital
Mice
Mice, Knockout
Microfilament Proteins
Muscle Proteins
Phenotype
Serum Response Factor