title: Ocular coloboma and dorsoventral neuroretinal patterning defects in Lrp6 mutant eyes.
abstract: Coloboma, an ocular birth defect seen in humans and other species, is caused by incomplete closure of the optic fissure. Here, we demonstrate that genetic deletion of Lrp6, a bottleneck coreceptor in the canonical Wnt signaling pathway, results in ocular coloboma and neuroretinal patterning defects in mice. The expression of ventral neuroretinal patterning gene Vax2 was conserved but with dorsally shifted expression domains; however, the dorsal neuroretinal patterning gene Tbx5 was lost in the Lrp6-mutant eyes at embryonic day 10.5. Both Bmp4 and phosphorylated Smad 1/5/8 were also significantly attenuated in the dorsal neuroretina. In addition, the retinoic acid synthesizing enzymes Raldh1 and Raldh3 were significantly changed in the mutant eyes. Our findings suggest that defective retinal patterning causes coloboma in the Lrp6-deficient mice, and that canonical Wnt signaling plays a primary role in dorsal neuroretinal patterning and related morphogenetic movements by regulation of both Bmp and retinoic acid signaling pathways.
authors.affiliation: Department of Cell Biology, School of Medicine, University of California, Davis, California, USA. cjzhou@ucdavis.edu
authors.forename: Cheng-Ji
authors.initials: CJ
authors.lastname: Zhou
authors.forename: Andrei
authors.initials: A
authors.lastname: Molotkov
authors.forename: Lanying
authors.initials: L
authors.lastname: Song
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Li
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pleasure
authors.forename: Ya-Zhou
authors.initials: YZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D003103:Coloboma / Q000196:embryology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D051153:Wnt Proteins; D014212:Tretinoin