Abstract
The vertebrate heart is assembled during embryogenesis in a modular manner from different populations of precursor cells. The right ventricular chamber and outflow tract are derived primarily from a population of progenitors known as the anterior heart field. These regions of the heart are severely hypoplastic in mutant mice lacking the myocyte enhancer factor 2C (MEF2C) and BOP transcription factors, suggesting that these cardiogenic regulatory factors may act in a common pathway for development of the anterior heart field and its derivatives. We show that Bop expression in the developing heart depends on the direct binding of MEF2C to a MEF2-response element in the Bop promoter that is necessary and sufficient to recapitulate endogenous Bop expression in the anterior heart field and its cardiac derivatives during mouse development. The Bop promoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF2. These findings identify Bop as an essential downstream effector gene of MEF2C in the developing heart, and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives.
Highlights
Heart development is a precisely orchestrated process in which even subtle perturbations can have catastrophic consequences for the organism
We show that Bop expression in the developing heart is downregulated in Mef2c mutant embryos, and we identify a MEF2-response element that controls expression of Bop in the anterior heart field during mouse embryogenesis. These findings identify Bop as an essential downstream effector gene of myocyte enhancer factor 2C (MEF2C) during formation of the right ventricular chamber and outflow tract (OFT) of the heart, and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives
Mouse embryos homozygous for a Mef2c null mutation die at E9.5 from severe cardiac abnormalities that include a failure of growth of the right ventricle (RV) and OFT (Lin et al, 1997)
Summary
Heart development is a precisely orchestrated process in which even subtle perturbations can have catastrophic consequences for the organism (reviewed by Fishman and Olson, 1997). Heart development begins when mesodermal progenitor cells within a bilaterally symmetric region of the embryo, known as the cardiac crescent or primary heart field, adopt a cardiac fate in response to inductive cues from the surrounding tissues (Fishman and Olson, 1997; Marvin et al, 2001; Schneider and Mercola, 2001; Schultheiss et al, 1997; Tzahor and Lassar, 2001). Soon thereafter, these cells converge along the midline of the embryo to form a linear heart tube that initiates peristaltic contractions. Further evidence for heterogeneity of cardiac precursors has come from the analysis of cis-regulatory elements associated with cardiac genes, which often direct expression in highly restricted regions of the developing heart (Biben and Harvey, 1997; Thomas et al, 1998)
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