The m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells

  1. Fugui Niu
  2. Peng Han
  3. Jian Zhang
  4. Yuanchu She
  5. Lixin Yang
  6. Jun Yu
  7. Mengru Zhuang
  8. Kezhen Tang
  9. Yuwei Shi
  10. Baisheng Yang
  11. Chunqiao Liu
  12. Bo Peng  Is a corresponding author
  13. Sheng-Jian Ji  Is a corresponding author
  1. Southern University of Science and Technology, China
  2. Chinese Academy of Sciences, China
  3. Sun Yat-sen University, China
  4. Fudan University, China

Abstract

The precise control of growth and maintenance of the retinal ganglion cell (RGC) dendrite arborization is critical for normal visual functions in mammals. However, the underlying mechanisms remain elusive. Here we find that the m6A reader YTHDF2 is highly expressed in the mouse RGCs. Conditional knockout (cKO) of Ythdf2 in the retina leads to increased RGC dendrite branching, resulting in more synapses in the inner plexiform layer. Interestingly, the Ythdf2 cKO mice show improved visual acuity compared with control mice. We further demonstrate that Ythdf2 cKO in the retina protects RGCs from dendrite degeneration caused by the experimental acute glaucoma model. We identify the m6A-modified YTHDF2 target transcripts which mediate these effects. This study reveals mechanisms by which YTHDF2 restricts RGC dendrite development and maintenance. YTHDF2 and its target mRNAs might be valuable in developing new treatment approaches for glaucomatous eyes.

Data availability

The RIP-seq data have been deposited to the Gene Expression Omnibus (GEO) with accession number GSE145390. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD017775.

The following data sets were generated

Article and author information

Author details

  1. Fugui Niu

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Peng Han

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Jian Zhang

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuanchu She

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Lixin Yang

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jun Yu

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Mengru Zhuang

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Kezhen Tang

    Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuwei Shi

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Baisheng Yang

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Chunqiao Liu

    Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Bo Peng

    Department of Neurosurgery, Fudan University, Shanghai, China
    For correspondence
    peng@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4183-5939
  13. Sheng-Jian Ji

    Department of Biology, Southern University of Science and Technology, Shenzhen, China
    For correspondence
    jisj@sustech.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3380-258X

Funding

National Natural Science Foundation of China (31871038)

  • Sheng-Jian Ji

National Natural Science Foundation of China (32170955)

  • Sheng-Jian Ji

National Natural Science Foundation of China (31922027)

  • Bo Peng

National Natural Science Foundation of China (32170958)

  • Bo Peng

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments using mice were carried out following the animal protocols approved by the Laboratory Animal Welfare and Ethics Committee of Southern University of Science and Technology (approval numbers: SUSTC-JY2017004, SUSTC-JY2019081).

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Version history

  1. Received: November 24, 2021
  2. Preprint posted: December 7, 2021 (view preprint)
  3. Accepted: February 16, 2022
  4. Accepted Manuscript published: February 18, 2022 (version 1)
  5. Version of Record published: March 9, 2022 (version 2)
  6. Version of Record updated: March 14, 2022 (version 3)
  7. Version of Record updated: April 4, 2022 (version 4)

Copyright

© 2022, Niu 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.

Metrics

  • 1,621
    Page views
  • 356
    Downloads
  • 12
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Fugui Niu
  2. Peng Han
  3. Jian Zhang
  4. Yuanchu She
  5. Lixin Yang
  6. Jun Yu
  7. Mengru Zhuang
  8. Kezhen Tang
  9. Yuwei Shi
  10. Baisheng Yang
  11. Chunqiao Liu
  12. Bo Peng
  13. Sheng-Jian Ji
(2022)
The m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells
eLife 11:e75827.
https://doi.org/10.7554/eLife.75827

Further reading

    1. Chromosomes and Gene Expression
    2. Neuroscience
    Alan E Murphy, Nurun Fancy, Nathan Skene
    Research Article

    Mathys et al. conducted the first single-nucleus RNA-seq (snRNA-seq) study of Alzheimer’s disease (AD) (Mathys et al., 2019). With bulk RNA-seq, changes in gene expression across cell types can be lost, potentially masking the differentially expressed genes (DEGs) across different cell types. Through the use of single-cell techniques, the authors benefitted from increased resolution with the potential to uncover cell type-specific DEGs in AD for the first time. However, there were limitations in both their data processing and quality control and their differential expression analysis. Here, we correct these issues and use best-practice approaches to snRNA-seq differential expression, resulting in 549 times fewer DEGs at a false discovery rate of 0.05. Thus, this study highlights the impact of quality control and differential analysis methods on the discovery of disease-associated genes and aims to refocus the AD research field away from spuriously identified genes.

    1. Neuroscience
    Josue Haubrich, Karim Nader
    Research Article

    The strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using c-fos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.