title: The spinster homolog, two of hearts, is required for sphingosine 1-phosphate signaling in zebrafish.
abstract: The bioactive lipid sphingosine 1-phosphate (S1P) and its G protein-coupled receptors play critical roles in cardiovascular, immunological, and neural development and function. Despite its importance, many questions remain about S1P signaling, including how S1P, which is synthesized intracellularly, is released from cells. Mutations in the zebrafish gene encoding the S1P receptor Miles Apart (Mil)/S1P(2) disrupt the formation of the primitive heart tube. We find that mutations of another zebrafish locus, two of hearts (toh), cause phenotypes that are morphologically indistinguishable from those seen in mil/s1p2 mutants. Positional cloning of toh reveals that it encodes a member of the Spinster-like family of putative transmembrane transporters. The biological functions of these proteins are poorly understood, although phenotypes of the Drosophila spinster and zebrafish not really started mutants suggest that these proteins may play a role in lipid trafficking. Through gain- and loss-of-function analyses, we show that toh is required for signaling by S1P(2). Further evidence indicates that Toh is involved in the trafficking or cellular release of S1P.
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, Cardiovascular Research Institute, University of California, San Francisco, 1550 Fourth Street, San Francisco, CA 94143, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Osborne
authors.forename: Koroboshka
authors.initials: K
authors.lastname: Brand-Arzamendi
authors.forename: Elke A
authors.initials: EA
authors.lastname: Ober
authors.forename: Suk-Won
authors.initials: SW
authors.lastname: Jin
authors.forename: Heather
authors.initials: H
authors.lastname: Verkade
authors.forename: Nathalia Glickman
authors.initials: NG
authors.lastname: Holtzman
authors.forename: Deborah
authors.initials: D
authors.lastname: Yelon
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D008246:Lysophospholipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D038081:Organogenesis; D010641:Phenotype; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D008565:Membrane Proteins; D049349:Receptors, Lysosphingolipid; D029961:Zebrafish Proteins; C454859:spns1 protein, zebrafish; C060506:sphingosine 1-phosphate; D013110:Sphingosine