Foxh1 Is Essential for Development of the Anterior Heart Field

Abstract

The anterior heart field (AHF) mediates formation of the outflow tract (OFT) and right ventricle (RV) during looping morphogenesis of the heart. Foxh1 is a forkhead DNA binding transcription factor in the TGFbeta-Smad pathway. Here we demonstrate that Foxh1-/- mutant mouse embryos form a primitive heart tube, but fail to form OFT and RV and display loss of outer curvature markers of the future working myocardium, similar to the phenotype of Mef2c-/- mutant hearts. Further, we show that Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene. This element directs transgene expression to the presumptive AHF, as well as the RV and OFT, a pattern that closely parallels endogenous Mef2c expression in the heart. Thus, Foxh1 and Nkx2-5 functionally interact and are essential for development of the AHF and its derivatives, the RV and OFT, in response to TGFbeta-like signals.

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;.…”

“…Recent reports highlight the importance of MEF2C in formation and transcriptional regulation of AHF-derived structures, leading to the hypothesis that part of the mef2c Ϫ/Ϫ phenotype can be explained as defects in AHF-derived structures (Dodou et al, 2004;von Both et al, 2004). Because the AHF-derived cells in the mef2c Ϫ/Ϫ embryo are capable of incorporating into the heart relatively normally, the dysfunction appears to be in later stages of development (Verzi et al, 2005).…”

“…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). Within the AHF, isl1 directly regulates transcription of the mef2c gene in combination with GATA factors through an element 5Ј of the transcriptional start site (Dodou et al, 2004).…”

“…Within the AHF, isl1 directly regulates transcription of the mef2c gene in combination with GATA factors through an element 5Ј of the transcriptional start site (Dodou et al, 2004). 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).…”

MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines

“…[29][30][31][32][33][34][35][36][37][38][39] Most genes were neither expressed in PEER nor in CCRF-CEM as analyzed by RT-PCR. However, five genes (CALR, CRIPTO, JMJD2A, MEF2C and PITX2) were expressed in both cell lines, while NR2F2 was expressed in PEER only, indicating their potential activation by NKX2-5.…”