September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Ablation of Crb1 and Crb2 Specifically in Mouse Müller Cells mimics early onset Retinitis Pigmentosa
Author Affiliations & Notes
  • Peter M Quinn
    Ophthalmology , Leiden University Medical Center , Leiden, Netherlands
  • Jan Wijnholds
    Ophthalmology , Leiden University Medical Center , Leiden, Netherlands
  • Footnotes
    Commercial Relationships   Peter Quinn, None; Jan Wijnholds, None
  • Footnotes
    Support  Foundation Fighting Blindness: TA-GT-0811-0590-NIN, TA-GT-0313-0607-NIN. The Netherlands Organisation For Health Research and Development: ZonMw grant 43200004
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2271. doi:
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      Peter M Quinn, Jan Wijnholds; Ablation of Crb1 and Crb2 Specifically in Mouse Müller Cells mimics early onset Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2271.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Human Crumbs homologue-1 gene mutations lead to severe inherited retinal dystrophies. Mouse Crb1 is localised in only Müller cells and Crb2 in both Müller and photoreceptor cells. Removal of either mouse Crb1 or Crb2 in Müller cells leads to a mild retinal degeneration suggesting overlapping functions for the two proteins. But we have yet to fully allude to how much overlap in function there might be. Here, we studied the loss of Crb1 with concurrent loss of Crb2 from Müller cells to address this.

Methods : Crb1 knockout mice were crossed with a retinal Crb2- Pdgfrα-Cre conditional knockout mouse strain in order to ablate Crb1 and Crb2 during retinal development from Müller cells. Retinas from various ages were analysed. Morphology was assed using toluidine blue staining of plastic-embedded sections. Immunohistochemistry (IHC) was carried out to allude to any ectopic localization of cells or intracellular proteins. In vivo analyses of retinal function were performed using electroretinography (ERG).

Results : Retinas with Müller cells lacking both Crb1 and Crb2 results in severe retinal disorganisation. First retinal aberrations are detected at P1, and at P14 this disorganisation is confined to the outer nuclear layer showing thinning of photoreceptor rows with severer areas having large rosette like structures, and unlike the other Crb double knockouts has only sporadic ectopic cells in the ganglion cell layer. At 5 months of age, scotopic ERG showed a severe attenuation of the a-wave and b-wave. These retinas no longer had a separate photoreceptor layer nor an outer plexiform layer, and ectopic RPE along with neovascularization of blood vessels from the choroid into the neural retina. IHC staining with recoverin showed a single sparse row of photoreceptors sitting on top of a disorganised inner nuclear layer with irregular localisation of SOX9 positive Müller cells. Further progressive total retinal thinning is seen from 5 to 10 months.

Conclusions : Conjoint loss of both Crb1 and Crb2 specifically in mouse Müller cells mimics early onset retinitis pigmentosa, whereas loss of Crb1 or Crb2 in Müller cells mimics late onset retinitis pigmentosa. Both Crb proteins provide some compensation for the other in Müller cells and Crb2 is not redundant therefore in this cell type. This suggests that total CRB levels in Müller cells in mice and men are important for maintenance of a structured retina.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.


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