April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Crx E168d2, an Autosomal Dominant Mouse Model for Cone-Rod Dystrophy, Exhibits a Genetic Interaction with Otx2 in Mature Photoreceptors
Author Affiliations & Notes
  • Nicholas M. Tran
    Molecul Genetics & Genomics, Washington Univ in St Louis, St Louis, Missouri
  • Shiming Chen
    Molecul Genetics & Genomics, Washington Univ in St Louis, St Louis, Missouri
  • Footnotes
    Commercial Relationships  Nicholas M. Tran, None; Shiming Chen, None
  • Footnotes
    Support  NIH: EY012543, EY012543-10S1, EY002687 (to WU-DOVS) and EY013360 (to WU); RBP: Lew R. Wasserman Award and unrestricted funds (to DOVS); FFB Individual Investigator Award; Hope for Vision Visionary Awa
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 5390. doi:
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      Nicholas M. Tran, Shiming Chen; Crx E168d2, an Autosomal Dominant Mouse Model for Cone-Rod Dystrophy, Exhibits a Genetic Interaction with Otx2 in Mature Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5390.

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

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Abstract

Purpose: : Dominant mutations of the transcription factor CRX cause retinopathies with a wide range of clinical phenotypes even given the same allele. At ARVO 2010, we introduced the Crx E168d2 knock-IN mouse as an animal model for dominant cone-rod dystrophy. E168d2 causes impaired cone function and slow cone degeneration. OTX2, a CRX family member that plays overlapping yet distinct roles with CRX during retinal development, is upregulated in homozygous E168d2 mice. In normal mature photoreceptors, CRX is expressed more robustly than OTX2 and acts as a critical activator of photoreceptor gene expression, while OTX2 is dispensable. Our goal was to determine if Otx2 acts as a genetic modifier of the photoreceptor pathology in E168d2 mice.

Methods: : Otx2 was selectively deleted from differentiated rods or cones in the Crx E168d2 mouse using Cre-loxP technology. The resulting E168d2/+; Otx2-/- rods and cones were characterized for changes in photoreceptor survival and morphology (histology, immuno-histochemistry), function (electroretinogram) and gene expression (QRTPCR, western blots).

Results: : Removal of Otx2 from wild-type rods or cones did not cause changes in retinal function, morphology or CRX target gene expression. However, loss of Otx2 in rods of E168d2/+ mice increased both rod and cone disease severity. By 1-2 months of age, these mice have shortened rod outer segments, strongly impaired rod function, reduced CRX target gene expression and degeneration of both rods and cones. Loss of Otx2 in cones of E168d2/+ mice caused accelerated cone degeneration and loss of cone function but did not affect rod function or survival.

Conclusions: : Despite normally playing a limited role in differentiated photoreceptors, loss of Otx2 in either rods or cones amplified E168d2 disease severity. This identifies Otx2 as a genetic modifier of E168d2. Our results demonstrate how genetic interactions can dramatically impact disease pathology.

Keywords: transcription factors • photoreceptors • gene modifiers 
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