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

Abstract

Coordinated cell migration is essential in many fundamental biological processes including embryonic development, organogenesis, wound healing and the immune response. During organogenesis, groups of cells are directed to specific locations within the embryo. Here we show that the zebrafish miles apart (mil) mutation specifically affects the migration of the heart precursors 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 fail to migrate, suggesting that mil may be involved in generating an environment permissive for migration. We isolated mil by positional cloning and show that it encodes a member of the lysosphingolipid G-protein-coupled receptor family. We also show that sphingosine-1-phosphate is a ligand for Mil, and that it activates several downstream signalling events that are not activated by the mutant alleles. These data reveal a new role for lysosphingolipids in regulating cell migration during vertebrate development and provide the first molecular clues into the fusion of the bilateral heart primordia during organogenesis of the heart.

Cardiac patterning and morphogenesis in zebrafish

“…At the 19-somite stage, cardiac fusion is under way in the wild-type embryo, but the myocardiocytes in the mil mutant embryo have not moved to the midline. As shown above for cas, these cells will remain in bilateral positions (Kupperman et al, 2000).…”

“…The precise nature of this signal is not yet known. However, generation or reception of this signal seems to involve the function of miles apart (mil), which encodes a lysosphingolipid G-protein-coupled receptor (Kupperman et al, 2000). Mutation of mil causes cardia bifida without disrupting gut formation or myocardial differentiation (Fig.…”

Expression patterns of the lysophospholipid receptor genes during mouse early development

“…Although these two genes appear to have diverged early in phylogeny, the similarity of the cis-elements that drive their expression in the developing heart seems to have been maintained. It is noteworthy that, in zebrafish, a mutation in S1p 2 called miles apart results in fusion of the bilateral heart tubes, or cardia bifida (Kupperman et al, 2000); the analogous phenotype is not observed in S1p 2 -null mice , suggesting that multiple members of the LPA/S1P receptor family likely contribute to heart morphogenesis in these species.…”

Sphingolipids and membrane biology as determined from genetic models

“…S1P 2 receptor-null mice are apparently normal at birth, with no anatomical defects, but between weeks 3 and 7, 59% of them are affected by sporadic seizures that are occasionally lethal (14% die) [180]. Interestingly, a mutation in a similar gene in zebrafish leads to embryonic lethality [181]. Therefore S1P 2 receptors could affect either microscopic development or membrane excitability by affecting intracellular calcium.…”