June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
The BXD32 mouse, a polygenic model of early onset inherited retinal dystrophy, degenerates from a loss of proper outer segment axonemic ciliogenesis and disc morphogenesis
Author Affiliations & Notes
  • TJ Hollingsworth
    Ophthalmology, The University of Tennessee Health Science Center Department of Ophthalmology Hamilton Eye Institute, Memphis, Tennessee, United States
  • Bahar Meshkat
    Ophthalmology, The University of Tennessee Health Science Center Department of Ophthalmology Hamilton Eye Institute, Memphis, Tennessee, United States
  • Xiangdi Wang
    Ophthalmology, The University of Tennessee Health Science Center Department of Ophthalmology Hamilton Eye Institute, Memphis, Tennessee, United States
  • William A White
    Ophthalmology, The University of Tennessee Health Science Center Department of Ophthalmology Hamilton Eye Institute, Memphis, Tennessee, United States
  • Esther Marquez-Wilkins
    Neuroscience Institute, The University of Tennessee Health Science Center College of Medicine, Memphis, Tennessee, United States
  • Monica M Jablonski
    Ophthalmology, The University of Tennessee Health Science Center Department of Ophthalmology Hamilton Eye Institute, Memphis, Tennessee, United States
  • Footnotes
    Commercial Relationships   TJ Hollingsworth None; Bahar Meshkat None; Xiangdi Wang None; William White None; Esther Marquez-Wilkins None; Monica Jablonski None
  • Footnotes
    Support  Knight's Templar Eye Foundation Career Starter Grant; Research to Prevent Blindness Challenge Grant; Research to Prevent Blindness/International Retina Research Foundation Catalyst Award for Innovative Research Approaches for Age-Related Macular Degeneration
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1538. doi:
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      TJ Hollingsworth, Bahar Meshkat, Xiangdi Wang, William A White, Esther Marquez-Wilkins, Monica M Jablonski; The BXD32 mouse, a polygenic model of early onset inherited retinal dystrophy, degenerates from a loss of proper outer segment axonemic ciliogenesis and disc morphogenesis. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1538.

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

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Abstract

Purpose : Inherited retinal dystrophies (IRDs) are a leading cause of congenital blindness. While rarer than other blinding diseases like glaucoma and age-related macular degeneration, many IRDs are more devastating due to vision loss in early childhood and blindness by or before adulthood. Many genes are known to cause IRDs when mutated and depending on the gene and mutation, can cause primary death of either rod or cone photoreceptors and, ultimately, both. The purpose of this work is to elucidate the cellular/molecular mechanisms of pathogenesis underlying the degeneration observed in a spontaneous, polygenic IRD mouse model, the BXD32 mouse.

Methods : As the BXD32 mouse descends from interbreeding between C57B/6J (B6) and DBA/2J (D2) mice, we used a comparison of protein sequence data (Ensembl) for the gene products of over 150 known IRD-associated genes in B6 and D2 mice to determine if the BXD32 mice harbor predicted deleterious nonsynonymous single nucleotide polymorphisms (SNPs). To assess the BXD32 retina for function, protein localization, and ultrastructure, we used electroretinography (ERG), fluorescent immunohistochemistry (fIHC), and transmission electron microscopy (TEM), respectively.

Results : BXD32 has predicted deleterious nonsynonymous SNPs in several IRD genes including Fscn2, Myo7a, Prom1, Rpgrip1, and Ush2a, all genes associated with cilia/disc formation. ERGs show a steady decline of a and b wave amplitudes from as early as p21 - p42. fIHC analysis shows aberrant outer segment formation, loss of outer limiting membrane integrity, and mislocalized opsins and MERTK. TEM revealed discs forming vertically and in whirls from the base of the outer segment up the axoneme but with a normal 9+0 bundle of microtubules.

Conclusions : The BXD32 mouse retina exhibits an early onset and rapid degeneration affecting cones and rods toward the central retina and extending to the periphery. While connecting cilia still appear to form from the basal body, formation and orientation of discs and the ciliary axoneme beyond the base of the outer segment are altered creating a dysmorphogenic outer segment in both cones and rods and subsequent cell death.

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

 

BXD32 mouse retina labeled for critical ciliary and outer segment proteins RPGR (red), CEP290 (green) and acetylated TUBA1 (blue). Nuclei labeled with DAPI (grey).

BXD32 mouse retina labeled for critical ciliary and outer segment proteins RPGR (red), CEP290 (green) and acetylated TUBA1 (blue). Nuclei labeled with DAPI (grey).

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