Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons
- West Virginia University, United States
Abstract
Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD+ homeostasis for health and function, the specific roles of subcellular NAD+ pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, transcriptomic and immunostaining approaches reveal dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.
Data availability
Sequencing data have been deposited in GEO under accession code GSE178312. All other data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
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Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neuronsNCBI Gene Expression Omnibus, GSE178312.
Article and author information
Author details
Saravanan Kolandaivelu
Funding
West Virginia University (Bridge Funding)
- Saravanan Kolandaivelu
National Institutes of Health (RO1EY028959)
- Saravanan Kolandaivelu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Paola Bovolenta, CSIC-UAM, Spain
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of West Virginia University. The protocol was approved by the Institutional Animal Care and Use Committee of West Virginia University (Protocol #1603001820).
Version history
- Preprint posted: May 5, 2021 (view preprint)
- Received: June 11, 2021
- Accepted: December 7, 2021
- Accepted Manuscript published: December 8, 2021 (version 1)
- Version of Record published: January 12, 2022 (version 2)
Copyright
© 2021, Sokolov et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons
eLife 10:e71185.
https://doi.org/10.7554/eLife.71185
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