Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart.

Abstract:

: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.

authors

Niu Z,Iyer D,Conway SJ,Martin JF,Ivey K,Srivastava D,Nordheim A,Schwartz RJ

doi

10.1073/pnas.0805491105

subject

Has Abstract

pub_date

2008-11-18 00:00:00

pages

17824-9

issue

46

eissn

0027-8424

issn

1091-6490

pii

0805491105

journal_volume

105

pub_type

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