September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Loss of Ikbkap Leads to Slow, Progressive Degeneration of Retinal Ganglion Cells in a Mouse Model of Familial Dysautonomia
Author Affiliations & Notes
  • Yumi Ueki
    Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, United States
  • Grisela Ramirez
    Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado, United States
  • Maureen E Stabio
    Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado, United States
  • Frances Lefcort
    Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, United States
  • Footnotes
    Commercial Relationships   Yumi Ueki, None; Grisela Ramirez, None; Maureen Stabio, None; Frances Lefcort, None
  • Footnotes
    Support  NIH/NEI F32 EY023498-01A1
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2726. doi:
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    • Get Citation

      Yumi Ueki, Grisela Ramirez, Maureen E Stabio, Frances Lefcort; Loss of Ikbkap Leads to Slow, Progressive Degeneration of Retinal Ganglion Cells in a Mouse Model of Familial Dysautonomia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2726.

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

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Abstract

Purpose : Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by an intronic mutation in the inhibitor of kappa B kinase complex-associated protein (IKAP) gene (IKBKAP). While FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. Recent clinical studies of eyes of 30 FD patients using optical coherence tomography showed that FD patients displayed loss of the retinal nerve fiber layer predominantly in the maculopapillary region, suggesting retinal ganglion cell (RGC) death. The purpose of our study was to develop a mouse model in which Ikbkap is selectively deleted from RGCs and to determine their fate in the absence of IKAP.

Methods : We generated Ikbkap CKO mice using a TUBA1a promoter-Cre (Tα1-Cre). Tα1-Cre mice were crossed to Cre-reporter in order to assess cell types expressing Cre. Retinas of Ikbkap CKO and control littermates were collected at 1mo, 3mo, 6mo, and 9mo, and the number of RGCs at 1mm from the optic nerve head at temporal, nasal, superior, and inferior retinas were counted using RGC markers (RBPMS, Brn3, melanopsin). Overall retinal morphology was assessed by H&E staining at various ages.

Results : Cre-reporter analysis of the retina at P10 showed Cre expression in approximately 90% of RGCs while expression in other retinal cell types was minimal. At 6mo, significant loss of RGCs was observed in the CKO retinas. The reduction in RGCs was greatest in the temporal retina, which corresponds to the clinical observation of FD patients. At 9mo, temporal retina of the CKO showed indications of photoreceptor degeneration. At 19mo, CKO retinas displayed pan-retinal degeneration including RGC loss, optic nerve thinning, photoreceptor loss, Müller glial activation, and disruption of layers.

Conclusions : Loss of Ikbkap in RGCs causes slow, progressive RGC degeneration predominantly in the temporal retina. The phenotype of our CKO recapitulates the clinical observation of human FD patients. This mouse model of FD blindness is not only useful for identifying the mechanisms mediating RGC degeneration but also provides a model system in which to attempt to rescue the phenotype as a proof of concept for mitigating the loss of vision in FD patients.

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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