Restricted inactivation of serum response factor to the cardiovascular system.
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.
Miano
Joseph M
JM
Center for Cardiovascular Research, Aab Institute of Biomedical Sciences, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA. j.m.miano@rochester.edu
Ramanan
Narendrakumar
N
Georger
Mary A
MA
de Mesy Bentley
Karen L
KL
Emerson
Rachael L
RL
Balza
Robert O
RO
Xiao
Qi
Q
Weiler
Hartmut
H
Ginty
David D
DD
Misra
Ravi P
RP
D000818:Animals; D018376:Cardiovascular Abnormalities; D002319:Cardiovascular System / Q000166:cytology / Q000196:embryology / Q000254:growth & development*; D004622:Embryo, Mammalian; D005317:Fetal Growth Retardation; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010641:Phenotype; D026362:Serum Response Factor / Q000172:deficiency / Q000502:physiology*
D008840:Microfilament Proteins; D009124:Muscle Proteins; D026362:Serum Response Factor; C058992:Tagln protein, mouse