June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Absence of Cone Photoreceptor Outer Segments in atf6-/- Anole Lizards – a New Research Model for Cone-Dystrophies
Author Affiliations & Notes
  • Heike Kroeger
    Cellular Biology, University of Georgia, Athens, Georgia, United States
  • Christina Sabin
    Neuroscience, University of Georgia, Athens, Georgia, United States
  • Jacob A. Holub
    Cellular Biology, University of Georgia, Athens, Georgia, United States
  • Douglas B. Menke
    Genetics, University of Georgia, Athens, Georgia, United States
  • James D Lauderdale
    Cellular Biology, University of Georgia, Athens, Georgia, United States
  • Footnotes
    Commercial Relationships   Heike Kroeger None; Christina Sabin None; Jacob Holub None; Douglas Menke None; James Lauderdale None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3214. doi:
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      Heike Kroeger, Christina Sabin, Jacob A. Holub, Douglas B. Menke, James D Lauderdale; Absence of Cone Photoreceptor Outer Segments in atf6-/- Anole Lizards – a New Research Model for Cone-Dystrophies. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3214.

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

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Abstract

Purpose :
ATF6 is a transcription factor with essential roles in cell stress signaling, stem cell differentiation, and tissue development. The loss of ATF6 function mutation has been linked to the development of the hereditary color-blinding disease achromatopsia (ACHM). Using retinal organoids from patient-derived iPSCs, we identified that ATF6 signaling is essential for cone photoreceptor development, primarily impacting the outer segment (OS). Conversely, the lack of appropriate research models has limited our advancement to investigate the regulatory mechanism of ATF6 signaling during cone photoreceptor development, maturation, and function. We propose that the cone-rich and bi-foveated brown anole lizard presents a valuable research tool to investigate disease phenotypes of cone-dystrophies, such as ACHM.

Methods :
CRISPR-Cas9 technology was used to generate atf6-/- anole lizards by injecting unfertilized oocytes of adult lizards. Hatchling eyes were collected for molecular and histological analysis. Dehydrated paraffin-embedded tissue was prepared for H&E staining and confocal microscopy, visualizing morphological features and retinal-specific cell types, focusing on cone photoreceptors. Wildtype hatchlings were used as controls.

Results :
We identified that genetically engineered atf6-/- lizards harbor the same cellular phenotype as previously identified in our ATF6 ACHM patients and our ATF6-/- iPSC retinal organoid model. Using markers for M/L cone opsin, we identified the absence of cone photoreceptor OS as seen in our wildtype controls. H&E staining correlated to this finding showing a thinning of the OS of the photoreceptor layer and an overall smaller ocular size when compared to wildtype hatchlings.

Conclusions :
The cone-rich retina of the brown lizard is a novel research model to investigate cone-dystrophies, such as ATF6-associated ACHM, providing an opportunity to investigate OS formation and regeneration under the control of ATF6 signaling. A detailed transcriptome analysis will further reveal the ATF6-dependent regulation of cone photoreceptor OS formation. The lizard additionally presents an innovative translational research model allowing advanced research studies that foster future therapeutic applications for a wide variety of cone-dystrophies.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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