A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development

Coordinated cell migration is essential in many fundamental biological proc esses including embryonic development, organogenesis, wound healing and the immune response. During organogenesis, groups of cells are directed to spe cific locations within the embryo. Here we show that the zebrafish miles ap art (mil) mutation(1,2) specifically affects the migration of the heart pre cursors to the midline. We found that mutant cells transplanted into a wild -type embryo migrate normally and that wild-type cells in a mutant embryo f ail to migrate, suggesting that mil may be involved in generating an enviro nment permissive for migration. We isolated mil by positional cloning and s how that it encodes a member of the lysosphingolipid G-protein-coupled rece ptor family. We also show that sphingosine-1-phosphate is a ligand for Mil, and that it activates several downstream signalling events that are not ac tivated by the mutant alleles. These data reveal a new role for lysosphingo lipids in regulating cell migration during vertebrate development and provi de the first molecular clues into the fusion of the bilateral heart primord ia during organogenesis of the heart.