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Kiana Kakavand, Andrew Ian Jobling, Robbert De Iongh, Stephane Chappaz, Benjamin T. Kyle, Erica L Fletcher; The role of pro-apoptotic proteins Bak and Bax in rd1 rodent model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5373.
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© ARVO (1962-2015); The Authors (2016-present)
In retinal degeneration, such as retinitis pigmentosa (RP), apoptosis is the common pathway involved in photoreceptor death. The mitochondrial-mediated pathway requires the activation of the Bcl-2 family members Bak and Bax, without which this form of apoptosis cannot proceed. The purpose of this study is to determine whether Bax and/or Bak have a role in the degeneration observed in the rd1 mouse model of RP.
Bak-/-and Bax-/- on a C57Bl6/J background were bred with C57Bl6/Jrd1/rd1 mice to generate mice with C57Bl6rd1/rd1/Bak-/-/Bax+/+, C57Bl6rd1/rd1/Bak-/-/Bax+/- and C57Bl6rd1/rd1/Bak-/-/Bax-/- genotypes. Eyes were collected at post-natal day (P) 14, 18 and 21 and the structure of the retina was assessed morphometrically using 5 µm haematoxylin and eosin stained paraffin sections. Rd1 retinas with Bax and Bak mutations were compared to C57Bl6rd1/rd1and C57bl6/J controls (n>6).
Genetic ablation of Bak with or without a Bax null allele (C57Bl6rd1/rd1/Bak-/-/Bax+/- and C57Bl6rd1/rd1/Bak-/-/Bax+/+) resulted in a slightly thicker outer nuclear layer (ONL) compared to the age-matched C57Bl6rd1/rd1 controls at P14 (27.5 ± 1 µm and 25.6 ± 0.4 µm compared to 20.9 ± 0.4 µm, p<0.0001), but no significant diffrences in total retinal thickness. The thickness of ONL and total retina remained significantly less than C57BL6 mice (142.1 ± 2.4 µm and 138.7 ± 2.7 µm compared to 185.36 ± 3.1 µm- p<0.0001). This increase in outer retinal thickness was transient, with no significant differences found at P18 and P21 among Bax/Bak/rd1 mutant and rd1 mice. While deletion of both Bak and Bax is associated with neonatal lethality, a single animal survived until P13. The ONL and total retina (65.1 µm and 291.3 µm) were considerably thicker than Bak-/-/Bax+/+/rd1 and rd1.
Genetic elimination of Bak, with or without heterozygosity for Bax, in the rd1 mouse caused a transient rescue of photoreceptor cells at early stages of retinal degeneration (P14). However, deletion of both Bak and Bax resulted in rescue of cell death at P13. These data suggest both Bak and Bax are involved in photoreceptor degeneration in the rd1 mouse, and that they may act redundantly.
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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