Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND

Abstract

dHAND and eHAND are related basic helix-loop-helix (bHLH) transcription factors that are expressed in mesodermal and neural crest-derived structures of the developing heart. In contrast to their homogeneous expression during avian cardiogenesis, during mouse heart development we show that dHAND and eHAND are expressed in a complementary fashion and are restricted to segments of the heart tube fated to form the right and left ventricles, respectively. dHAND and eHAND represent the earliest cardiac chamber-specific transcription factors yet identified. Targeted gene deletion of dHAND in mouse embryos resulted in embryonic lethality at embryonic day 10.5 from heart failure. Our description of the cardiac phenotype of dHAND mutant embryos is the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches and reveals a novel cardiogenic subprogramme for right ventricular development.

Gene duplications, robustness and evolutionary innovations

“…Mice express two duplicates of Hand. Among other defects, loss-of-function mutants in Hand1 are defective in left ventricle formation, whereas loss of function mutants in Hand2 fail to form the right ventricle [73][74][75][76] . The functions of two duplicates have become partitioned such that each is associated with formation of a morphological partition of an organ.…”

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

“…Hand1 expression begins in the posterior, ventral part of the linear tube and then moves anteriorly as looping proceeds. It is thus a very early marker of the subdivision of the primitive left ventricle into primary and secondary ventricular myocardium (Biben and Harvey, 1997;Srivastava et al, 1997). During looping, its posterior expression in the linear tube relocates to the left and expression begins in the OFT and RV (Biben and Harvey, 1997;Srivastava et al, 1997).…”

“…It is thus a very early marker of the subdivision of the primitive left ventricle into primary and secondary ventricular myocardium (Biben and Harvey, 1997;Srivastava et al, 1997). During looping, its posterior expression in the linear tube relocates to the left and expression begins in the OFT and RV (Biben and Harvey, 1997;Srivastava et al, 1997). For our analysis, Hand1lacZ reporter mice in which the lacZ gene replaces most of the first coding exon of hand1 were crossed with mef2c ϩ/Ϫ mice in a scheme similar to that used by Firulli and coworkers (Firulli and Thattaliyath, 2002;Morikawa and Cserjesi, 2004).…”

“…Early evidence of the importance of MEF2 activity in transcriptional regulation of AHF-derivatives was the finding that the mlc2v and desmin promoters, which are specific to the OFT and RV, require MEF2 binding sites (Kuisk et al, 1996;Ross et al, 1996). 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).…”

Cardiac patterning and morphogenesis in zebrafish

“…For example, although hand2 regulates early aspects of myocardial differentiation in zebrafish, hand2 mutant mice do not exhibit cardiac defects until after heart tube formation (Srivastava et al, 1997). One possible explanation for this discrepancy is that the related mouse gene hand1 may be able to compensate for a loss of hand2 function at early stages.…”