Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 46, Pages 17824-17829Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0805491105
Keywords
heart development; microRNA; periostin; cardiogenesis; GATA6
Categories
Funding
- National Institutes of Health
- Fondation Leducq Transatlantic Network of Excellence for Cardiovascular Research
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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 Hand 1 and Smyd 1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom 1, 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 SRIF point mutants that block cofactor interactions. In the absence of SRIF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRIF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.
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