THE HAND1 BHLH TRANSCRIPTION FACTOR IS ESSENTIAL FOR PLACENTATION ANDCARDIAC MORPHOGENESIS

The placenta and cardiovascular system are the first organ systems to form during mammalian embryogenesis. We show here that a single gene i s critical for development of both. The Hand1 gene, previously called Hxt, eHAND and Thing1, encodes a basic helix-loop-helix (bHLH) transcr iption factor that starts to be expressed during pre-implantation deve lopment. After implantation, Hand1 expression is restricted to placent al trophoblast cells and later to embryonic cardiac and neural crest c ells(1-3). We generated Hand1-null mutant mice by gene targetting. Hom ozygous mutant embryos arrested by embryonic day (E) 7.5 of gestation with defects in trophoblast giant cell differentiation. This early mor tality could be rescued by aggregation of mutant embryos with wild-typ e tetraploid embryos, which contribute wild-type cells to the trophobl ast, but not the embryo. By E10.5, however, the Hand1-null fetuses der ived from tetraploid chimaeras died due to cardiac failure. Their hear t tubes showed abnormal looping and ventricular myocardial differentia tion. Therefore, Hand1 is essential for differentiation of both tropho blast and cardiomyocytes, which are embryologically distinct cell line ages.