Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons

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.

The following data sets were generated

Article and author information

Author details

  1. David Sokolov

    Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Emily R Sechrest

    Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yekai Wang

    Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Connor Nevin

    Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jianhai Du

    Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Saravanan Kolandaivelu

    Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States
    For correspondence
    kolandaivelus@hsc.wvu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8552-7850

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

  1. 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

  1. Preprint posted: May 5, 2021 (view preprint)
  2. Received: June 11, 2021
  3. Accepted: December 7, 2021
  4. Accepted Manuscript published: December 8, 2021 (version 1)
  5. 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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  1. David Sokolov
  2. Emily R Sechrest
  3. Yekai Wang
  4. Connor Nevin
  5. Jianhai Du
  6. Saravanan Kolandaivelu
(2021)
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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https://doi.org/10.7554/eLife.71185

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