A Hand for the Epicardium

See related article, pages 940–949In mammals, formation of the properly septated 4-chambered heart and coronary vasculature is essential for unidirectional blood flow and survival of the organism. This process involves complex cell-cell interactions, the dysregulation of which can profoundly alter organogenesis, leading to a plethora of structural or functional cardiac defects. No wonder that congenital heart disease (CHD) represents the largest class of birth defects in humans. CHD, even the more subtle, subclinical form, is a major risk factor for early onset of serious cardiovascular complications and premature death. Despite important advances in diagnosis and surgical repair, preventive or therapeutic approaches have been hampered by our incomplete understanding of the molecular basis of most CHDs.Over the past 15 years, work in several model systems has identified genes required for normal heart development and started unraveling intricate regulatory relationships among many of them. Importantly, mutations in several of these cardiac regulators were subsequently linked to human CHD.1 Of those, the basic helix-loop-helix transcription factors Hand1 (eHAND) and Hand2 (dHAND) have emerged as important regulators of heart, limb, and neural crest cell development. Within the developing heart, Hand1 and Hand2 have overlapping expression in the cardiac crescent, but Hand1 expression becomes more restricted to the left ventricle after cardiac looping, whereas Hand2 becomes more localized to the right ventricle and derivatives of the secondary heart field (SHF).2 Gene targeting …