Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart.
Our conditional serum response factor (SRF) knockout, Srf (Cko), in the heart-forming region blocked the appearance of rhythmic beating myocytes, one of the earliest cardiac defects caused by the ablation of a cardiac-enriched transcription factor. The appearance of Hand1 and Smyd1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom1, myofibril proteins; and calcium-activated potassium-channel gene activity (KCNMB1), the channel protein, were powerfully attenuated in the Srf(CKO) mutant hearts. A requisite role for combinatorial cofactor interactions with SRF, as a major determinant for regulating the appearance of organized sarcomeres, was shown by viral rescue of SRF-null ES cells with SRF point mutants that block cofactor interactions. In the absence of SRF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.
Niu
Zhiyv
Z
Center for Cardiovascular Development, Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
Iyer
Dinakar
D
Conway
Simon J
SJ
Martin
James F
JF
Ivey
Kathryn
K
Srivastava
Deepak
D
Nordheim
Alfred
A
Schwartz
Robert J
RJ
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000648:ultrastructure; D005110:Extracellular Space / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D024510:Muscle Development; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism* / Q000648:ultrastructure; D026362:Serum Response Factor / Q000172:deficiency / Q000378:metabolism*
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D050993:GATA6 Transcription Factor; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C082838:Postn protein, mouse; D026362:Serum Response Factor