Roles of Nmnat1 in the survival of retinal progenitors through the regulation of pro-apoptotic gene expression via histone acetylation

Cell Death & Disease
Hiroshi KuribayashiSumiko Watanabe

Abstract

Leber congenital amaurosis (LCA) is a severe, genetically heterogeneous dystrophy of the retina and mutations in the nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) gene is one of causal factors of LCA. NMNAT1 is a nuclear enzyme essential for nicotinamide adenine dinucleotide (NAD) biosynthesis pathways, but the mechanisms underlying the LCA pathology and whether NMNAT1 has a role in normal retinal development remain unclear. Thus, we examined the roles of Nmnat1 in retinal development via short hairpin (sh)-RNA-mediated downregulation. Retinal explants expressing sh-Nmnat1 showed large numbers of apoptotic retinal progenitor cells in the inner half of the neuroblastic layer. Decreased intracellular NAD content was observed and the addition of NAD to the culture medium attenuated sh-Nmnat1-induced apoptosis. Of the nuclear Sirtuin (Sirt) family, the expression of sh-Sirt1 and sh-Sirt6 resulted in a phenotype similar to that of sh-Nmnat1. Sirt proteins are histone deacetylases and the expression of sh-Nmnat1 increased the levels of acetylated histones H3 and H4 in the retina. Expression of sh-Nmnat1 resulted in significantly increased expression of Noxa and Fas, two pro-apoptotic genes. Acetylation of the genomic 5'-...Continue Reading

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Citations

Mar 28, 2020·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Daisy UmutoniSumiko Watanabe
May 27, 2020·Oxidative Medicine and Cellular Longevity·Ravirajsinh N JadejaPamela M Martin
Jul 10, 2019·Nutritional Neuroscience·Keisuke HikosakaTakashi Nakagawa
Aug 28, 2018·Biochemical and Biophysical Research Communications·Yuichi KawamuraSumiko Watanabe

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Methods Mentioned

BETA
PCR
immunoprecipitation
Assay
RNA-seq
transfection
acetylation

Software Mentioned

Axio Image M2
Zeiss Image
Zeiss
Axio Image

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis