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Lucie Pellissier, Ditte Lundvig, Celso H. Alves, Alicia Sanz Sanz, Susanne C. Beck, Gesine Huber, Naoyuki Tanimoto, Mathias Seeliger, Jan Wijnholds; CRB1 and CRB2 In Retinal Development - Part 1. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4339.
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Mutations in the Crumbs homologue 1 (Crb1) gene are associated with early and severe vision loss. CRB1 belongs to a protein family comprising CRB1-3. The function of CRB1 is not well known. Mice lacking CRB1 demonstrate retinal degeneration in one quadrant of the eye, and this spatial restriction of pathology may be due to overlapping functions of the other CRB proteins. To address this, we generated and analyzed Crb1-Crb2 double knockout mice to study the functional consequence hereof in the retina.
Crb1 knockout mice were crossed with a retinal Crb2-Chx10Cre knockout mouse strain. Animals of different ages were analyzed. Morphological analysis was done with toluidine blue staining of plastic-embedded sections. To study possible ectopic localizations of proteins and cells, immunohistochemistry (IHC) was done on retinas. Optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO) and electroretinography (ERG) will be presented in Part 2.
Retinas from mice lacking both CRB1 and CRB2 show already from P1 a progressed disorganization accompanied by photoreceptor disorganization, where only two nuclear layers (NL) and an inner plexiform layer are evident. This disorganization is seen throughout the whole retina. Furthermore, from P1 and up to 1 month of age, these mice demonstrate rosette-like structures in the outer NL. IHC stainings with cell-specific nuclear markers demonstrate that all retinal cell types are present despite the loss of the photoreceptor nuclear layer. However, the different retinal cell types display ectopic localization in the different layers. ERG demonstrated a compromised retinal function from 1 month of age, and OCT showed a thinning of the retina, starting from 3 months of age.
Loss of both CRB1 and CRB2 results in a more severe phenotype than in the Crb1 and Crb2 knockout mice, suggesting that CRB1 and CRB2 may have overlapping as well as unique functions in retina development.
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