title: Targeted inactivation of serum response factor in the developing heart results in myocardial defects and embryonic lethality.
abstract: Serum response factor (SRF) is at the confluence of multiple signaling pathways controlling the transcription of immediate-early response genes and muscle-specific genes. There are active SRF target sequences in more than 50 genes expressed in the three muscle lineages including normal and diseased hearts. However, the role of SRF in heart formation has not been addressed in vivo thus far due to the early requirement of SRF for mesoderm formation. We have generated a conditional mutant of SRF by using Cre-LoxP strategy that will be extremely useful to study the role of SRF in embryonic and postnatal cardiac functions, as well as in other tissues. This report shows that heart-specific deletion of SRF in the embryo by using a new beta MHC-Cre transgenic mouse line results in lethal cardiac defects between embryonic day 10.5 (E10.5) and E13.5, as evidenced by abnormally thin myocardium, dilated cardiac chambers, poor trabeculation, and a disorganized interventricular septum. At E9.5, we found a marked reduction in the expression of essential regulators of heart development, including Nkx2.5, GATA4, myocardin, and the SRF target gene c-fos prior to overt maldevelopment. We conclude that SRF is crucial for cardiac differentiation and maturation, acting as a global regulator of multiple developmental genes.
authors.affiliation: Laboratoire de Biologie Moléculaire de la Différenciation, Université Paris 7, 75005 Paris, France.
authors.forename: Ara
authors.initials: A
authors.lastname: Parlakian
authors.forename: David
authors.initials: D
authors.lastname: Tuil
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Hamard
authors.forename: Geneviève
authors.initials: G
authors.lastname: Tavernier
authors.forename: Daniele
authors.initials: D
authors.lastname: Hentzen
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Concordet
authors.forename: Denise
authors.initials: D
authors.lastname: Paulin
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Li
authors.forename: Dominique
authors.initials: D
authors.lastname: Daegelen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005313:Fetal Death; D005318:Fetal Heart / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005865:Gestational Age; D006330:Heart Defects, Congenital / Q000196:embryology / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009928:Organ Specificity; D011247:Pregnancy; D026362:Serum Response Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D026362:Serum Response Factor; D014157:Transcription Factors