title: Sphingosine 1-phosphate receptors are essential mediators of eyelid closure during embryonic development.
abstract: The fetal development of the mammalian eyelid involves the expansion of the epithelium over the developing cornea, fusion into a continuous sheet covering the eye, and a splitting event several weeks later that results in the formation of the upper and lower eyelids. Recent studies have revealed a significant number of molecular signaling components that are essential mediators of eyelid development. Receptor-mediated sphingosine 1-phosphate (S1P) signaling is known to influence diverse biological processes, but its involvement in eyelid development has not been reported. Here, we show that two S1P receptors, S1P2 and S1P3, are collectively essential mediators of eyelid closure during murine development. Homozygous deletion of the gene encoding either receptor has no apparent effect on eyelid development, but double-null embryos are born with an "eyes open at birth" defect due to a delay in epithelial sheet extension. Both receptors are expressed in the advancing epithelial sheet during the critical period of extension. Fibroblasts derived from double-null embryos have a deficient response to epidermal growth factor, suggesting that S1P2 and S1P3 modulate this essential signaling pathway during eyelid closure.
authors.affiliation: From the Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037 and.
authors.forename: Deron R
authors.initials: DR
authors.lastname: Herr
authors.forename: Chang-Wook
authors.initials: CW
authors.lastname: Lee
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Adam
authors.initials: A
authors.lastname: Ware
authors.forename: Richard
authors.initials: R
authors.lastname: Rivera
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005124:Eye Abnormalities / Q000196:embryology / Q000235:genetics; D005143:Eyelids / Q000196:embryology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011247:Pregnancy; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; D004815:Epidermal Growth Factor; D013110:Sphingosine
keywords: Development; ERK; Epidermal Growth Factor (EGF); Eye; G Protein-coupled Receptors (GPCRs); Gene Knockout; MAP Kinases (MAPKs); Mouse; Sphingolipid; Sphingosine 1-Phosphate