title: CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina.
abstract: Mutations within the CRB1 gene have been shown to cause human retinal diseases including retinitis pigmentosa and Leber congenital amaurosis. We have recently identified a mouse model, retinal degeneration 8 (rd8) with a single base deletion in the Crb1 gene. This mutation is predicted to cause a frame shift and premature stop codon which truncates the transmembrane and cytoplasmic domain of CRB1. Like in Drosophila crumbs (crb) mutants, staining for adherens junction proteins known to localize to the external limiting membrane, the equivalent of the zonula adherens in the mammalian retina, is discontinuous and fragmented. Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. The Crb1rd8 mouse model will facilitate the analysis of Crb1 function in the neural retina and the identification of interacting factors as candidate retinal disease genes.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Adrienne K
authors.initials: AK
authors.lastname: Mehalow
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kameya
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.forename: Norman L
authors.initials: NL
authors.lastname: Hawes
authors.forename: James M
authors.initials: JM
authors.lastname: Denegre
authors.forename: James A
authors.initials: JA
authors.lastname: Young
authors.forename: Lesley
authors.initials: L
authors.lastname: Bechtold
authors.forename: Neena B
authors.initials: NB
authors.lastname: Haider
authors.forename: Ulrich
authors.initials: U
authors.lastname: Tepass
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Naggert
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism; D002874:Chromosome Mapping; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology* / Q000378:metabolism; D020033:Protein Isoforms; D012160:Retina / Q000196:embryology* / Q000254:growth & development; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology; D029702:Schizosaccharomyces pombe Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C453730:Crb1 protein, mouse; C109867:Crb2 protein, S pombe; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D029702:Schizosaccharomyces pombe Proteins