June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Photoreceptor expression of functional Crx is required to maintain retinal pigment epithelium and retinal vasculature integrity.
Author Affiliations & Notes
  • Jerome E Roger
    NEUROPSI, CERTO / CNRS, Orsay, France
  • Elodie-Kim Grellier
    NEUROPSI, CERTO / CNRS, Orsay, France
  • Nareh Sahakian
    NEUROPSI, CERTO / CNRS, Orsay, France
  • Muriel Perron
    NEUROPSI, CERTO / CNRS, Orsay, France
  • Footnotes
    Commercial Relationships   Jerome Roger, None; Elodie-Kim Grellier, None; Nareh Sahakian, None; Muriel Perron, None
  • Footnotes
    Support  Association Retina France and Fondation Valentin Haüy. Idex Paris-Saclay. CNRS
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5372. doi:
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      Jerome E Roger, Elodie-Kim Grellier, Nareh Sahakian, Muriel Perron; Photoreceptor expression of functional Crx is required to maintain retinal pigment epithelium and retinal vasculature integrity.
      . Invest. Ophthalmol. Vis. Sci. 2017;58(8):5372.

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

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Abstract

Purpose : We previously identified a spontaneous mouse mutant with a dominant frameshift mutation in the photoreceptor-expressed gene Crx (CrxRip) causing congenital blindness due to arrested photoreceptor differentiation. Photoreceptors degenerate in CrxRip/Rip mice while they are preserved for an extended period of time in CrxRip/+. Since they represent an excellent pre-clinical model, we initiated an in-depth characterization of both autonomous and non-autonomous effects during aging of CrxRip mice to better assess future therapeutic outcomes.

Methods : Histology and TUNEL staining were used to assess photoreceptor loss in CrxRip/Rip compared to CrxRip/+ mice. Immunohistochemical analyses were performed on retinal sections and flat mount retinal pigment epithelium (RPE). The retina and the vasculature were observed by fundus imaging and angiography, respectively. Gene expression analysis was performed at P21 by RNA-Seq.

Results : In CrxRip/+ mice, limited photoreceptor apoptosis was detected up to P30. Müller cell activation was observed from P30 onward. The integrity of the retinal vasculature was preserved (up to 7 months). Fundus imaging showed a slight pigmentation of the back of the eye from P60 but a good preservation of the RPE. In contrast, a large number of photoreceptors died in CrxRip/Rip mouse retina starting at P21 with a peak at P30 and a complete loss at 7 months. Concomitantly, Müller cell interkinetic migration occurs into the photoreceptor layer. Massive blood leakage occurred as early as P30, when the thickness of the outer nuclear layer is not significantly decreased compared to control and CrxRip/+ retina. Unexpectedly, massive RPE atrophy was observed starting at P30 from the center to the periphery. In comparison, such large defects were observed in rd10 mice but only weeks after complete loss of rods. Using RNA-Seq data from P21, we are currently seeking for deregulated genes causing the non-cell autonomous effects observed in CrxRip/Rip retina compared to CrxRip/+.

Conclusions : Our work revealed that lack of functional CRX in CrxRip/Rip photoreceptors not only impairs their survival but also leads to massive RPE atrophy and retinal vasculature defects. Such non-cell autonomous defects strongly suggest that CRX regulates photoreceptor-expressed factors required for RPE and retinal vasculature maintenance and yet to be identified.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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