SEROTONIN AND CARDIAC MORPHOGENESIS IN THE MOUSE EMBRYO

The possible involvement of the neurotransmitter serotonin (5-HT) and its binding protein (SBP) in cardiac morphogenesis was studied using m ouse whole embryo culture (together with immunocytochemistry or H-3-th ymidine autoradiography) and a cell migration assay. Embryos were cult ured before and during the period of endocardial cushion formation, em bryonic (E) days 9-12, in the presence of 5-HT, the monoamine oxidase (MAO) inhibitor nialamide, or an uptake inhibitor (fluoxetine or sertr aline). For the migration assay, cells from the outflow tracts of E12 embryos were dissociated and placed in a chemotaxis chamber together w ith different concentrations of 5-HT. E9 embryos cultured in the prese nce of 10 muM 5-HT and nialamide exhibited intense 5-HT immunoreactivi ty (5-HT IR) throughout the myocardium. This staining was greatly dimi nished by fluoxetine, sertraline, or the absence of nialamide. As morp hogenesis proceeded, myocardial staining in embryos exposed to 5-HT be came restricted to developing endocardial cushion forming regions and was more completely blocked by uptake inhibitors. No evidence for 5-HT synthesis by myocardium was found at any age studied using the precur sor L-tryptophan. SBP was present in endocardial cushions in cultured and uncultured embryos. H-3-thymidine autoradiography demonstrated tha t both fluoxetine and sertraline inhibited proliferation of cardiac me senchyme, endocardium, and myocardium. These effects were most pronoun ced when exposure began at E9 (prior to cushion formation). Dose-depen dent effects of 5-HT on migration of outflow tract cells were also obs erved. Taken together, these results suggest that 5-HT may play a role in cardiac morphogenesis during endocardial cushion formation.