Targeted deletion of Nmnat1 in mouse retina leads to early severe retinal dystrophy

Abstract

Mutations in NMNAT1 can lead to a very severe type of retinal dystrophy, Leber congenital amaurosis, in human patients, characterized by infantile-onset or congenital retinal dystrophy and childhood blindness. The loss-of-function mouse models of Nmnat1 have not been well-established, since the complete knock-out (KO) of Nmnat1 in mice results in embryonic lethality. Here, we generated retina-specific KO by using the Crxpromotor-driving Cre combined with the flox allele. By a panel of histological and functional analyses, we found that Nmnat1 conditional KO (cKO) mice have early severe retinal dystrophy. Specifically, the photoreceptors of Nmnat1 cKO mice are almost diminished and the retinal functions also become completely abolished. Our results established a loss-of-function model for Nmnat1 in mice, which will be useful for studying the detailed functions of NMNAT1 in the retina.peer-reviewed)

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

“…In mutant animals in which Nmnat1 was excised, we observed a complete loss of both scotopic (rod-driven responses) and photopic (cone-driven responses) responses, indicating the loss of Nmnat1 in mature retina causes severe photoreceptor dysfunction ( Figure 2C–E ). This is consistent with previous reports showing developmental retinal defects in the tissue specific Nmnat1 knockout mice ( Eblimit et al, 2018 ; Wang et al, 2017 ). While previous reports show that Nmnat1 is necessary for appropriate retinal development, our pathological and functional analyses of conditional deletion of NMNAT1 in two-month-old mice demonstrates that NMNAT1 is also necessary for photoreceptor cell maintenance and mature retinal functions.…”

“…NMNAT1 plays important roles in diverse retinal functions. Overexpression of NMNAT1 in mouse retinal ganglion cells (RGCs) robustly protects against ischemic and glaucomatous loss of the axon and soma ( Zhu et al, 2013 ), while conditional ablation in the developing mouse retina causes severe retinal dystrophy and loss of retinal function ( Eblimit et al, 2018 ; Wang et al, 2017 ). Mice harboring Nmnat1 mutations (V9M and D243G) exhibit severe retinal degeneration while the most common LCA9 mutation (E257K), which is not fully penetrant ( Siemiatkowska et al, 2014 ), induces a milder retinal degeneration phenotype ( Eblimit et al, 2018 ; Greenwald et al, 2016 ).…”

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

“…In mutant animals in which NMNAT1 was excised, we observed a complete loss of both scotopic (rod-driven responses) and photopic (cone-driven responses) responses, indicating the loss of Nmnat1 in mature retina causes severe photoreceptor dysfunction ( Figure 3D-F). This is consistent with previous reports showing developmental retinal defects in the tissue specific NMNAT1 knockout mice 11,12 . While previous reports show that NMNAT1 is necessary for appropriate retinal development, our pathological and functional analyses of two-month-old mice show that NMNAT1 is necessary for photoreceptor cell maintenance and mature retinal functions.…”

“…We analyzed the retinas of Nmnat1 fl/fl :Rhodopsin-Cre mice at 6-weeks-of-age. Similar to previous findings 11,12 , histological analysis revealed severe thinning of the ONL in these mutant mice ( Figure 4A, B), with a significant reduction in cell number as detected by nuclear counts ( Figure 4E). There was also a much smaller decrease in the number of cells in the INL.…”

“…in mouse retinal ganglion cells (RGCs) robustly protects against ischemic and glaucomatous loss of the axon and soma 10 , while conditional ablation in the developing mouse retina causes severe retinal dystrophy and loss of retinal function 11,12 . Mice harboring Nmnat1 mutations (V9M and D243G) exhibit severe retinal degeneration while the most common LCA9 mutation (E257K), which is not fully penetrant 13 , induces a milder retinal degeneration phenotype 11,14 .…”