title: Wnt ligands from the embryonic surface ectoderm regulate 'bimetallic strip' optic cup morphogenesis in mouse.
abstract: The Wnt/β-catenin response pathway is central to many developmental processes. Here, we assessed the role of Wnt signaling in early eye development using the mouse as a model system. We showed that the surface ectoderm region that includes the lens placode expressed 12 out of 19 possible Wnt ligands. When these activities were suppressed by conditional deletion of wntless (Le-cre; Wls(fl/fl)) there were dramatic consequences that included a saucer-shaped optic cup, ventral coloboma, and a deficiency of periocular mesenchyme. This phenotype shared features with that produced when the Wnt/β-catenin pathway co-receptor Lrp6 is mutated or when retinoic acid (RA) signaling in the eye is compromised. Consistent with this, microarray and cell fate marker analysis identified a series of expression changes in genes known to be regulated by RA or by the Wnt/β-catenin pathway. Using pathway reporters, we showed that Wnt ligands from the surface ectoderm directly or indirectly elicit a Wnt/β-catenin response in retinal pigment epithelium (RPE) progenitors near the optic cup rim. In Le-cre; Wls(fl/fl) mice, the numbers of RPE cells are reduced and this can explain, using the principle of the bimetallic strip, the curvature of the optic cup. These data thus establish a novel hypothesis to explain how differential cell numbers in a bilayered epithelium can lead to shape change.
authors.affiliation: Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: April C
authors.initials: AC
authors.lastname: Carpenter
authors.affiliation: Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: April N
authors.initials: AN
authors.lastname: Smith
authors.affiliation: Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Wagner
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Ramat Aviv, Tel Aviv 6997801, Israel.
authors.forename: Yamit
authors.initials: Y
authors.lastname: Cohen-Tayar
authors.affiliation: Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Rao
authors.affiliation: Vision Science Research Program, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Wallace
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Ramat Aviv, Tel Aviv 6997801, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.affiliation: Visual Systems Group, Abrahamson Pediatric Eye Institute, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA richard.lang@cchmc.org.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
mesh_terms: D000818:Animals; D004475:Ectoderm / Q000378:metabolism*; D047108:Embryonic Development; D005123:Eye / Q000196:embryology* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C545200:Gpr177 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D043562:Receptors, G-Protein-Coupled; D014212:Tretinoin
keywords: Morphogenesis; Optic cup; Wnt ligands