BOP, a regulator of right ventricular heart development, is a direct transcriptional target of MEF2C in the developing heart

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 Boppromoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF2. These findings identify Bopas 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.

MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field

“…The role of MEF2C in AHF differentiation is beginning to be defined through promoter and mutant analyses. This research places mef2c downstream of isl1 and foxh1, and upstream of bop and hand2 for transcriptional regulation within the AHF and its derivatives (Cai et al, 2003;Dodou et al, 2004;von Both et al, 2004;Phan et al, 2005). However, AHF defects alone do not explain the reduced size and transcriptional abnormalities in the LV, hich is formed exclusively from the PHF, nor the absence of a morphologically normal AVC, which is derived from both fields (Cai et al, 2003;.…”

“…Similarly, foxh1 regulates transcription of mef2c in combination with nkx2.5 through a 3Ј element (von Both et al, 2004). Importantly, deletion of either isl1 or foxh1 causes loss of the RV, supporting a genetic pathway for formation of the AHF-derived structures from isl1 and foxh1 through mef2c to bop, hand2, and perhaps other downstream effectors Cai et al, 2003;von Both et al, 2004;Phan et al, 2005).…”

“…Paradoxically, deletion of a known MEF2C target, bop, results in a similar loss of the RV but an increase in extracellular matrix (Gottlieb et al, 2002;Phan et al, 2005).…”

“…This was followed by the observation that hand2 and bop are downregulated in the mef2c Ϫ/Ϫ heart and that deletion of either causes loss of the RV Srivastava et al, 1997;Gottlieb et al, 2002). Moreover, the bop promoter contains essential MEF2 sites, suggesting a genetic route from mef2c to RV formation through the direct activation of the bop promoter and the, possibly indirect, induction of hand2 expression (Phan et al, 2005). A potential upstream genetic pathway within the AHF from isl1 and foxh1 to mef2c has also been uncovered (Dodou et al, 2004;von Both et al, 2004).…”

smyd1 and smyd2 are expressed in muscle tissue in Xenopus laevis

“…The 5 varieties of smyd genes in M. musculus and H. sapiens have been cloned. It is well established that SMYD1 plays a role in normal development of heart in mouse (Hwang and Gottlieb 1997;Gottlieb et al 2002;Phan et al 2005) and muscle in zebrafish Tan et al 2006). Also, SMYD2 and SMYD3 are reported to might be involved in repression and activation of cell cycle (Brown et al 2006;Tsuge et al 2005;Hamamoto et al 2004).…”