Hand, an evolutionarily conserved bHLH transcription factor required for Drosophila cardiogenesis and hematopoiesis

Zhe Han, Peng Yi, Eric Olson. Dept Molecular Biol, Univ Texas SW Medical Ctr, Dallas, TX.

The Hand family of basic Helix-Loop-Helix (bHLH) transcription factors plays critical roles in cardiovascular development in vertebrates, but little is known about the single Hand gene in Drosophila. Here, we show that Drosophila Hand is expressed in cardioblasts, pericardial nephrocytes and hematopoietic progenitors. The homeodomain protein Tinman and the GATA factors, Pannier and Serpent, directly activate Hand in these cell types through a minimal enhancer, which is necessary and sufficient to drive Hand expression in these cell types composing the circulatory system. Using cell culture and in vivo over-expression assays, we show that Drosophila Hand is a potent transcriptional activator required for development of the heart and lymph gland. Disruption of Hand function by homologous recombination results in embryonic and larval lethality accompanied by profound heart defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic precursor cells, accompanied by ectopic apoptosis in these organs. These abnormalities can be rescued by targeted expression of a human Hand gene, as well as the caspase inhibitor p35. These findings place hand at a nexus of the transcriptional networks that govern cardiogenesis and hematopoiesis, and reveal evolutionarily conserved functions of Hand transcription factors in the control of cell survival during cardiogenesis and hematopoiesis.

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