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Bruce R. Ksander, Alexander Jones, Simon W. John, Ann Marshak-Rothstein, Meredith S. Gregory; Accelerated Glaucoma And Increased Neurotoxicity In DBA/2J Mice That Cannot Cleave Fas Ligand. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2449.
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© ARVO (1962-2015); The Authors (2016-present)
All forms of glaucoma share a common endpoint, the loss of retinal ganglion cells (RGCs). While evidence indicates RGCs undergo apoptosis, the actual molecular mechanisms controlling this are still controversial. Fas Ligand (FasL) is a pro-apoptotic protein that is constitutively expressed in the retina where it is thought to protect tissue from destruction by maintaining immune privilege. However, there are two forms of FasL, a membrane-bound form (mFasL) and a soluble form (sFasL) that is produced by metalloproteinase cleavage. Our previous studies indicate that mFasL is pro-apoptotic, while sFasL is anti-apoptotic. We recently developed a knock-in mouse in which the FasL metalloproteinase cleavage sites were mutated to prevent cleavage of the membrane-bound protein (termed ΔCS mice). These mice allowed us to study the in vivo function of membrane FasL in the absence of soluble FasL. In order to determine the function of mFasL during development of glaucoma, we backcrossed the ΔCS knock-in mutation into the DBA/2J strain (D2.ΔCS mice) that develops spontaneous elevated intraocular pressure (IOP) and loss of RGCs.
D2.ΔCS mice were compared with D2 littermates (D2.WT) and B6.ΔCS mice. Groups of mice were aged up to 12 months and examined for age-related: (i) IOP (Tonolab), (ii) iris atrophy and pigment dispersion, (iii) loss of RGCs, nerve fibers, and optic nerve axons (beta tubulin, SMI32, and PPD staining), and (iv) retinal degeneration (histological examination).
D2.WT and D2.ΔCS (from 3 - 12 months) displayed a similar age-related (i) increase in IOP, and (ii) pigment dispersion and iris atrophy. By contrast, retinal whole mounts at 5 months revealed a loss of nerve fibers and RGCs in D2.ΔCS, but not D2.WT mice. At 12 months, D2 mice display loss of only RGCs, but similarly aged D2.ΔCS mice displayed extensive retinal degeneration in all retinal layers. As a control for the ΔCS mutation alone, 10 month old ΔCS.B6 mice displayed normal retinal architecture and no loss of RGCs.
Our results indicate that mFasL is a critical mediator of RGC apoptosis during the development of glaucoma. Moreover, sFasL has an important neuroprotective effect that not only prevents loss of RGCs, but also protects other retinal neurons in hypertensive eyes.
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