The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis

Abstract

The placenta and cardiovascular system are the first organ systems to form during mammalian embryogenesis. We show here that a single gene is critical for development of both. The Hand1 gene, previously called Hxt, eHAND and Thing1, encodes a basic helix-loop-helix (bHLH) transcription factor that starts to be expressed during pre-implantation development. After implantation, Hand1 expression is restricted to placental trophoblast cells and later to embryonic cardiac and neural crest cells. We generated Hand1-null mutant mice by gene targetting. Homozygous mutant embryos arrested by embryonic day (E) 7.5 of gestation with defects in trophoblast giant cell differentiation. This early mortality could be rescued by aggregation of mutant embryos with wild-type tetraploid embryos, which contribute wild-type cells to the trophoblast, but not the embryo. By E10.5, however, the Hand1-null fetuses derived from tetraploid chimaeras died due to cardiac failure. Their heart tubes showed abnormal looping and ventricular myocardial differentiation. Therefore, Hand1 is essential for differentiation of both trophoblast and cardiomyocytes, which are embryologically distinct cell lineages.

Suppression of atrial myosin gene expression occurs independently in the left and right ventricles of the developing mouse heart

“…The expression pattern of dHAND is highly similar to the distribution of ␣-MHC, MLC1A, and MLC2A transcripts during this period, suggesting a potentially direct contribution to the regionalisation of these downstream genes. dHAND and eHAND have essential roles in early heart development: dHAND null mice die at E10.5 and lack a morphological RV (Srivastava et al, 1997) whereas eHAND null mice display abnormal cardiac looping in addition to yolk sac defects (Firulli et al, 1998;Riley et al, 1998). The early phenotype in each case precludes an investigation of later roles for dHAND and eHAND in modulating sarcomeric gene expression in a chamber-specific manner.…”

Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

“…It is likely that other factors contributed for vascular defects in the extraembryonic compartment. First, defects in vascular formation in the yolk sac were not described for mutant embryo for Hand1 (Riley et al, 1998), although heart formation arrested at the similar stage, and even some mutant mice showed extraembryonic defects in spite of their beating heart (Wang et al, 1997;Shreiber et al, 2000;Ishikawa et al, 2001). Second, the extraembryonic mesoderm, generated during gastrulation, gives rise to blood islands and blood vessels associated with the visceral yolk sac (Patan, 2000).…”

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.…”