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Hum Mol Genet. 2014 Jul 1;23(13):3384-401. doi: 10.1093/hmg/ddu048. Epub 2014 Feb 2.

Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa.

Author information

1
Department of Neuromedical Genetics.
2
Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University of Tübingen, Tübingen D-72076, Germany.
3
Department of Retinal Signal Processing and.
4
Institute for Protein Research & CREST-JST, Osaka University, Osaka, Japan Department of Developmental Biology, Osaka Bioscience Institute, Suita, Osaka, Japan and.
5
Department of Molecular and Cellular Biology and The Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA.
6
Department of Neuroregeneration, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
7
Department of Neuromedical Genetics, j.wijnholds@nin.knaw.nl.

Abstract

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 Müller 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 Müller 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 Müller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Müller 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 Müller glial cells, causes sporadic loss of adhesion between photoreceptors and Müller cells.

PMID:
24493795
DOI:
10.1093/hmg/ddu048
[Indexed for MEDLINE]
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