Targeted Ablation of Crb1 and Crb2 in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis

Pellissier, Lucie P.; Alves, Celso; Quinn, Peter M J; Vos, Rogier M.; Tanimoto, Naoyuki; Lundvig, Ditte M. S.; Dudok, Jacobus J.; Hooibrink, Berend; Richard, Fabrice; Beck, Susanne; Huber, Günter L.; Sothilingam, Vithiyanjali; Garrido, Marina Garcia; Bivic, André Le; Seeliger, Mathias W.; Wijnholds, Jan

doi:10.1371/journal.pgen.1003976

Cited by 71 publications

(104 citation statements)

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“…However, in contrast with the observation made in the Crb2Chx10 cKO (11,13), in the Crb2Crx cKO the lamination of ganglion, amacrine, bipolar and Müller glial cells was also affected, misplaced inner retinal cells were detected ectopically in the ONL. Similar defects in the lamination of these cells were also observed in CRB2 null retinas with half of the amount of CRB1 (Crb1 +/2 Crb2Chx10 cKO) (17). These results are in line with (i) previous zebrafish data where Crb2a is required for retinal cell patterning and lamination (30) and (ii) mouse data where the CRB-interacting protein PALS1 affected the correct patterning of photoreceptor cells (31,32).…”

Section: Discussionsupporting

confidence: 89%

“…We hypothesize that CRB1 in Müller glial cells (14,34) compensated in Crb2Pdgfra cKO retinas for the loss of CRB2. We recently demonstrated that removal of CRB1 in a CRB2 null retina exacerbate the CRB2 phenotype in a dosedependent manner (17). Thus, mouse retinas with complete depletion of CRB1 and CRB2 from Müller glial cells could answer this question.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of both CRB1 and CRB2, from mouse retinal progenitor cells, results in retinal overgrowth due to overproliferation of retinal progenitor cells, leading to an abnormal and thick retina without a proper and separated photoreceptor cell layer. The Crumbs proteins show a dose-dependent effect, since different levels of CRB protein give rise to different phenotypes (17).…”

Section: Introductionmentioning

confidence: 99%

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Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa

Alves¹,

Pellissier²,

Vos³

et al. 2014

Human Molecular Genetics

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In humans, the Crumbs homolog-1 (CRB1) gene is mutated in autosomal recessive Leber congenital amaurosis and early-onset retinitis pigmentosa. In mammals, the Crumbs family is composed of: CRB1, CRB2, CRB3A and CRB3B. Recently, we showed that removal of mouse Crb2 from retinal progenitor cells, and consequent removal from Mü ller glial and photoreceptor cells, results in severe and progressive retinal degeneration with concomitant loss of retinal function that mimics retinitis pigmentosa due to mutations in the CRB1 gene. Here, we studied the effects of cell-type-specific loss of CRB2 from the developing mouse retina using targeted conditional deletion of Crb2 in photoreceptors or Mü ller cells. We analyzed the consequences of targeted loss of CRB2 in the adult mouse retina using adeno-associated viral vectors encoding Cre recombinase and short hairpin RNA against Crb2. In vivo retinal imaging by means of optical coherence tomography on retinas lacking CRB2 in photoreceptors showed progressive thinning of the photoreceptor layer and cellular mislocalization. Electroretinogram recordings under scotopic conditions showed severe attenuation of the a-wave, confirming the degeneration of photoreceptors. Retinas lacking CRB2 in developing photoreceptors showed early onset of abnormal lamination, whereas retinas lacking CRB2 in developing Mü ller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Mü ller glial cells, while CRB2 has essential functions in photoreceptors. Our data suggest that short-term loss of CRB2 in adult mouse photoreceptors, but not in Mü ller glial cells, causes sporadic loss of adhesion between photoreceptors and Mü ller cells.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa

Alves¹,

Pellissier²,

Vos³

et al. 2014

Human Molecular Genetics

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“…The retinal laminar structure on SD OCT in our patient cohort was relatively intact compared with that of earlier studies that described coarse lamination, defined as unclearly delineated retinal layers, in mice and patients with CRB1-associated retinal dystrophies, in both thickened and atrophic areas of retina. 3,12,13,34 Although our findings suggest progressive over congenital changes, a limitation of this study is the lack of longitudinal OCT follow-up, which could clarify if such coarse OCT lamination is the result of a congenital or a degenerative process. The finding of peripheral loss of delineation with central islands of intact lamination in an RP phenotype with centripetal progression would support the notion of intact retinal lamination at birth followed by progressive retinal dystrophy with consequent loss of outer retinal lamination in the affected areas.…”

Section: Discussionmentioning

confidence: 70%

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

et al. 2017

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Purpose: To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies.Design: Retrospective cohort study. Participants: Fifty-five patients with CRB1-associated retinal dystrophies from 16 families. Methods: A medical record review of 55 patients for age at onset, medical history, initial symptoms, bestcorrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography.Main Outcome Measures: Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings.Results: A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0e55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly (P ¼ 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rodecone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients.Conclusions: Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life. Ophthalmology 2017;124:884-895 ª 2017 by the American Academy of Ophthalmology Supplemental material available at www.aaojournal.org.Mutations in the CRB1 gene are associated with a wide variety of severe retinal dystrophies with variable phenotypes, including panretinal dystrophies such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and coneerod dystrophy, as well as central phenotypes such as isolated macular dystrophy and foveal retinoschisis. Retinitis pigmentosa is a clinically and genetically heterogeneous disorder. Mutations in the CRB1 gene have been associated with RP12, a distinct form of RP characterized by preservation of para-arteriolar retinal pigment epithelium, progressive visual field (VF) loss starting from the first decade of life, and early macular involvement. 4 Other common features are hyperopia and optic disc drusen, previously described in a Dutch genetic isolate (GI). 5Classic forms of earl...

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“…Gross morphological defects are preceded by problems in the integrity of the zonula adherens (ZA; the outer limiting membrane of the vertebrate retina) that emerge during terminal differentiation of the retina, and a failure to form inner and/or outer segments of normal size. Crb1 Crb2 double mutants show more severe defects than Crb1 mutants and resemble human patients with Leber congenital amaurosis (Pellissier et al, 2013), suggesting that Crb2 also plays an important role in retinal development. Numerous disease-causing mutations in CRB1 have been reported in human patients ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Unique cell biological profiles of retinal disease-causing missense mutations in the polarity protein Crumbs

Pellikka¹,

Tepaß²

2017

Development

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Mutations in human crumbs 1 (CRB1) are a major cause of retinal diseases that lead to blindness. CRB1 is a transmembrane protein found in the inner segment of photoreceptor cells (PRCs) and the apical membrane of Müller glia. The function of the extracellular region of CRB1 is poorly understood, although more than 80 diseasecausing missense mutations have been mapped to it. We have recreated four of these mutations, affecting different extracellular domains, in Drosophila Crumbs (Crb). Crb regulates epithelial polarity and growth, and contributes to PRC differentiation and survival. The mutant Crb isoforms showed a remarkable diversity in protein abundance, subcellular distribution and ability to rescue the lack of endogenous Crb, elicit a gain-of-function phenotype or promote PRC degeneration. Interestingly, although expression of mutant isoforms led to a substantial rescue of the developmental defects seen in crb mutants, they accelerated PRC degeneration compared to that seen in retinas that lacked Crb, indicating that the function of Crb in cellular differentiation and cell survival depends on distinct molecular pathways. Several Crb mutant proteins accumulated abnormally in the rhabdomere and affected rhodopsin trafficking, suggesting that abnormal rhodopsin physiology contributes to Crb/CRB1-associated retinal degeneration.

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Targeted Ablation of Crb1 and Crb2 in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis

Cited by 71 publications

References 46 publications

Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa

Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

Unique cell biological profiles of retinal disease-causing missense mutations in the polarity protein Crumbs

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