title: Loss of CRB2 in the mouse retina mimics human retinitis pigmentosa due to mutations in the CRB1 gene.
abstract: In humans, the Crumbs homolog-1 (CRB1) gene is mutated in progressive types of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. However, there is no clear genotype-phenotype correlation for CRB1 mutations, which suggests that other components of the CRB complex may influence the severity of retinal disease. Therefore, to understand the physiological role of the Crumbs complex proteins, we generated and analysed conditional knockout mice lacking CRB2 in the developing retina. Progressive disorganization was detected during late retinal development. Progressive thinning of the photoreceptor layer and sites of cellular mislocalization was detected throughout the CRB2-deficient retina by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. Under scotopic conditions using electroretinography, the attenuation of the a-wave was relatively stronger than that of the b-wave, suggesting progressive degeneration of photoreceptors in adult animals. Histological analysis of newborn mice showed abnormal lamination of immature rod photoreceptors and disruption of adherens junctions between photoreceptors, Müller glia and progenitor cells. The number of late-born progenitor cells, rod photoreceptors and Müller glia cells was increased, concomitant with programmed cell death of rod photoreceptors. The data suggest an essential role for CRB2 in proper lamination of the photoreceptor layer and suppression of proliferation of late-born retinal progenitor cells.
authors.affiliation: Department of Neuromedical Genetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Celso Henrique
authors.initials: CH
authors.lastname: Alves
authors.forename: Alicia Sanz
authors.initials: AS
authors.lastname: Sanz
authors.forename: Bokyung
authors.initials: B
authors.lastname: Park
authors.forename: Lucie P
authors.initials: LP
authors.lastname: Pellissier
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.forename: Gesine
authors.initials: G
authors.lastname: Huber
authors.forename: Mariyam
authors.initials: M
authors.lastname: Murtaza
authors.forename: Fabrice
authors.initials: F
authors.lastname: Richard
authors.forename: Iswariyaraja
authors.initials: I
authors.lastname: Sridevi Gurubaran
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia Garrido
authors.forename: Christiaan N
authors.initials: CN
authors.lastname: Levelt
authors.forename: Penny
authors.initials: P
authors.lastname: Rashbass
authors.forename: André
authors.initials: A
authors.lastname: Le Bivic
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Jan
authors.initials: J
authors.lastname: Wijnholds
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D016133:Polymerase Chain Reaction; D012160:Retina / Q000254:growth & development / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D041623:Tomography, Optical Coherence
chemical_list: C448939:CRB1 protein, human; C568885:Crb2 protein, mouse; D017931:DNA Primers; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins