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.