5-HT2B RECEPTOR-MEDIATED SEROTONIN MORPHOGENETIC FUNCTIONS IN MOUSE CRANIAL NEURAL CREST AND MYOCARDIAL-CELLS

During embryogenesis, serotonin has been reported to be involved in cr aniofacial and cardiovascular morphogenesis. The detailed molecular me chanisms underlying these functions, however remain unknown, From mous e and human species, we have recently reported the cloning of 5-HT2B r eceptors which share signal transduction pathways with other 5-HT2 rec eptor subtypes (5-HT2A and 5-HT2C). In addition to phospholipase C sti mulation, it appears that these three subtypes of receptor transduce a common serotonin-induced mitogenic activity, which could be important for cell differentiation and proliferation, We have first investigate d the expression of 5-HT2 receptor mRNAs in the mouse embryo, Interest ingly, a peak of 5-HT2B receptor mRNA expression was detected 8-9 days postcoitum, whereas there was only low level 5-HT2A and no 5-HT2C rec eptor mRNA expression at this stage, Expression of this receptor was c onfirmed by binding assays using a 5-HT2-specific ligand which reveale d a peak of binding to membrane preparations from 9 days postcoitum em bryos, In addition, whole mount in situ hybridisation and immunohistoc hemistry on similar stage embryos detected 5-HT2B expression in neural crest cells, heart myocardium and somites; The requirement for functi onal 5-HT2B receptors between 8 and 9 days postcoitum is supported by culture of embryos exposed to 5-HT2-specific ligands; 5-HT2B high-affi nity antagonist such as ritanserin, induced morphological defects in t he cephalic region, heart and neural tube, These antagonistic treatmen ts interfere with cranial neural crest cell migration, induce their ap optosis, and are responsible for abnormal sarcomeric organisation of t he subepicardial layer and for the absence of the trabecular cell laye r in the ventricular myocardium, This report indicates for the first t ime that 5-HT2B receptors are actively mediating the action of seroton in on embryonic morphogenesis, probably by preventing the differentiat ion of cranial neural crest cells and myocardial precursor cells.