Serotonin 2B receptor is required for heart development

Several lines of evidence suggest that the serotonin (5-hydroxy-tryptamine, 5-HT) regulates cardiovascular functions during embryogenesis and adulthoo d. 5-HT binds to numerous cognate receptors to initiate its biological effe cts. However, none of the 5-HT receptor disruptions in mice have yet result ed in embryonic defects. Here we show that 5-HT2B receptor is an important regulator of cardiac development. We found that inactivation of 5-HT2B gene leads to embryonic and neonatal death caused by heart defects. 5-HT2B muta nt embryos exhibit a lack of trabeculae in the heart and a specific reducti on in the expression levels of a tyrosine kinase receptor, ErbB-2, leading to midgestation lethality. These in vivo data suggest that the Gq-coupled r eceptor 5-HT2B uses the signaling pathway of tyrosine kinase receptor ErbB- 2 for cardiac differentiation. All surviving newborn mice display a severe ventricular hypoplasia caused by impaired proliferative capacity of myocyte s. in adult mutant mice, cardiac histopathological changes including myocyt e disarray and ventricular dilation were consistently observed. Our results constitute genetic evidence that 5-HT via 5-HT2B receptor regulates differ entiation and proliferation of developing and adult heart. This mutation pr ovides a genetic model for cardiopathy and should facilitate studies of bot h the pathogenesis and therapy of cardiac disorders in humans.