KIT ligand protects against both light-induced and genetic photoreceptor degeneration

Abstract

Photoreceptor degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become readily available. Here we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

Data availability

Sequencing data have been deposited in GEO under accession codes 146176.All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1-supplment figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 5-fig supplement 1, Figure 8, Figure 9, Figure 9-supplment figure 1.

The following data sets were generated

Article and author information

Author details

  1. Huirong Li

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Lili Lian

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Bo Liu

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yu Chen

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jinglei Yang

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Shuhui Jian

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jiajia Zhou

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Ying Xu

    GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Xiaoyin Ma

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jia Qu

    Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Ling Hou

    Wenzhou Medical University, Wenzhou, China
    For correspondence
    lhou@eye.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0705-8099

Funding

National Natural Science Foundation of China (81800838)

  • Huirong Li

National Natural Science Foundation of China (81770946)

  • Ling Hou

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 animal experiments were carried out in accordance with the approved guidelines of the Wenzhou Medical University Institutional Animal Care and Use Committee (Permit Number: WZMCOPT-090316).

Copyright

© 2020, Li 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

  • 1,517
    views
  • 230
    downloads
  • 14
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Huirong Li
  2. Lili Lian
  3. Bo Liu
  4. Yu Chen
  5. Jinglei Yang
  6. Shuhui Jian
  7. Jiajia Zhou
  8. Ying Xu
  9. Xiaoyin Ma
  10. Jia Qu
  11. Ling Hou
(2020)
KIT ligand protects against both light-induced and genetic photoreceptor degeneration
eLife 9:e51698.
https://doi.org/10.7554/eLife.51698

Share this article

https://doi.org/10.7554/eLife.51698

Further reading

    1. Neuroscience
    Björn Herrmann
    Research Article

    Neural activity in auditory cortex tracks the amplitude-onset envelope of continuous speech, but recent work counterintuitively suggests that neural tracking increases when speech is masked by background noise, despite reduced speech intelligibility. Noise-related amplification could indicate that stochastic resonance – the response facilitation through noise – supports neural speech tracking, but a comprehensive account is lacking. In five human electroencephalography experiments, the current study demonstrates a generalized enhancement of neural speech tracking due to minimal background noise. Results show that (1) neural speech tracking is enhanced for speech masked by background noise at very high signal-to-noise ratios (~30 dB SNR) where speech is highly intelligible; (2) this enhancement is independent of attention; (3) it generalizes across different stationary background maskers, but is strongest for 12-talker babble; and (4) it is present for headphone and free-field listening, suggesting that the neural-tracking enhancement generalizes to real-life listening. The work paints a clear picture that minimal background noise enhances the neural representation of the speech onset-envelope, suggesting that stochastic resonance contributes to neural speech tracking. The work further highlights non-linearities of neural tracking induced by background noise that make its use as a biological marker for speech processing challenging.

    1. Neuroscience
    Donald Iain MacDonald, Monessha Jayabalan ... Alexander Theodore Chesler
    Research Article

    The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed, we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.