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Todd McLaughlin, Joshua Jianxin Wang, Sarah Xin Zhang; Loss of Xbp1 in retinal cells accelerates age-related deterioration in the mouse visual system.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5860.
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Extended age leads to retinal deterioration and visual system functional decline. X-box binding protein 1 (Xbp1) is a critical component of the Unfolded Protein Response to reduce endoplasmic reticulum (ER) stress. We hindered cellular stress responses by deleting Xbp1 from a subset of retinal cells to determine if naturally occurring stress over a long period (i.e. more than one year) contributes to age-related abnormalities in retinal structure and functional decline in mice.
Conditional knockout (cKO) of Xbp1 was achieved by crossing mice with floxed alleles of Xbp1 with a retina-specific Cre line (Chx10-cre). Cre deletes Xbp1 from a subset of retinal cells, including most or all bipolar cells, prior to maturation. Retinal morphology was examined with immunohistochemical markers in WT and cKO in retinal sections in adolescent and 12-15 month old mice. Visual function was assessed by dark- and light-adapted electroretinogram (ERG). Markers of ER stress in cKO and WT were examined by Western blot.
Young cKO mice are indistinguishable from WT. At 12-15 months old the WT visual system is essentially indistinguishable from young adult WT mice (e.g. two months old). However, 12-15 month old cKO mice have a significantly diminished ERG b-wave, compared to age-matched WT mice, which reflects reduction in the bipolar cell response. In addition, we find significantly more dendritic extensions into the outer nuclear layer (ONL) in cKO mice, and more ectopic synapses between bipolar cells and photoreceptors (PR) in the ONL of aged cKO compared to WT. These abnormalities mimic those shown to be due to PR axon retraction in mice over two years old. In aged cKO mice the retina is thinner than in WT, with a significant decrease in the number of retinal ganglion cells. Cell loss and retinal thinning are also present in mice over two years old.
The loss of Xbp1 compromises the ability of a cell to respond to the chronic stresses related to aging. Eventually, retina lacking Xbp1 in a subset of cells are less functional than WT littermates. We find that bipolar cells in the cKO are less functional than WT cells at an advanced age, and display several morphological attributes that mimic much older animals. We suggest that routine long term stress is detrimental to the visual system and age-related decline is accelerated in the absence of a robust ER stress response system.
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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