The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity

  1. Yeha Kim
  2. Soyeon Lim
  3. Taejeong Ha
  4. You-Hyang Song
  5. Young-In Sohn
  6. Dae-Jin Park
  7. Sun-Soon Paik
  8. Joo-ri Kim-Kaneyama
  9. Mi-Ryoung Song
  10. Amanda Leung
  11. Edward M Levine
  12. In-Beom Kim
  13. Yong Sook Goo
  14. Seung-Hee Lee
  15. Kyung Hwa Kang
  16. Jin Woo Kim  Is a corresponding author
  1. Korea Advanced Institute of Science and Technology, Republic of Korea
  2. Chungbuk National University School of Medicine, Republic of Korea
  3. The Catholic University of Korea, Republic of Korea
  4. Showa University School of Medicine, Japan
  5. Gwangju Institute of Science and Technology, Republic of Korea
  6. Vanderbilt University, United States
  7. KAIST Institute of BioCentury, Republic of Korea

Abstract

The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of Paired-homeobox 6 (PAX6) is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that Hydrogen peroxide-induced clone 5 (Hic5) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. Hic5-/- mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the Hic5-/- mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective Pax6ΔPBS/ΔPBS mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.

Article and author information

Author details

  1. Yeha Kim

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  2. Soyeon Lim

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Taejeong Ha

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. You-Hyang Song

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Young-In Sohn

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Dae-Jin Park

    Department of Physiology, Chungbuk National University School of Medicine, Cheongju, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Sun-Soon Paik

    Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  8. Joo-ri Kim-Kaneyama

    Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Mi-Ryoung Song

    Department of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. Amanda Leung

    Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Edward M Levine

    Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. In-Beom Kim

    Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  13. Yong Sook Goo

    Department of Physiology, Chungbuk National University School of Medicine, Cheongju, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  14. Seung-Hee Lee

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9486-5771
  15. Kyung Hwa Kang

    KAIST Institute of BioCentury, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  16. Jin Woo Kim

    Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    For correspondence
    jinwookim@kaist.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0767-1918

Funding

National Research Foundation of Korea (NRF-2009-00424)

  • Jin Woo Kim

National Research Foundation (NRF-2006-2004289)

  • Kyung Hwa Kang

National Eye Institute (NIH R01-EY013760)

  • Edward M Levine

National Research Foundation of Korea (NRF-2013-056566)

  • Jin Woo Kim

National Research Foundation of Korea (NRF-2014R1A2A2A01003069)

  • Jin Woo Kim

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 performed according to the regulations of the KAIST-IACUC (KA2012-38).

Copyright

© 2017, Kim 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

  • 1,878
    views
  • 391
    downloads
  • 19
    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. Yeha Kim
  2. Soyeon Lim
  3. Taejeong Ha
  4. You-Hyang Song
  5. Young-In Sohn
  6. Dae-Jin Park
  7. Sun-Soon Paik
  8. Joo-ri Kim-Kaneyama
  9. Mi-Ryoung Song
  10. Amanda Leung
  11. Edward M Levine
  12. In-Beom Kim
  13. Yong Sook Goo
  14. Seung-Hee Lee
  15. Kyung Hwa Kang
  16. Jin Woo Kim
(2017)
The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity
eLife 6:e21303.
https://doi.org/10.7554/eLife.21303

Share this article

https://doi.org/10.7554/eLife.21303

Further reading

    1. Chromosomes and Gene Expression
    Daphne R Knudsen-Palmer, Pravrutha Raman ... Antony M Jose
    Research Article

    Since double-stranded RNA (dsRNA) is effective for silencing a wide variety of genes, all genes are typically considered equivalent targets for such RNA interference (RNAi). Yet, loss of some regulators of RNAi in the nematode Caenorhabditis elegans can selectively impair the silencing of some genes. Here, we show that such selective requirements can be explained by an intersecting network of regulators acting on genes with differences in their RNA metabolism. In this network, the Maelstrom domain-containing protein RDE-10, the intrinsically disordered protein MUT-16, and the Argonaute protein NRDE-3 work together so that any two are required for silencing one somatic gene, but each is singly required for silencing another somatic gene, where only the requirement for NRDE-3 can be overcome by enhanced dsRNA processing. Quantitative models and their exploratory simulations led us to find that (1) changing cis-regulatory elements of the target gene can reduce the dependence on NRDE-3, (2) animals can recover from silencing in non-dividing cells, and (3) cleavage and tailing of mRNAs with UG dinucleotides, which makes them templates for amplifying small RNAs, are enriched within ‘pUG zones’ matching the dsRNA. Similar crosstalk between pathways and restricted amplification could result in apparently selective silencing by endogenous RNAs.

    1. Chromosomes and Gene Expression
    Shuvra Shekhar Roy, Sulochana Bagri ... Shantanu Chowdhury
    Research Article

    Although the role of G-quadruplex (G4) DNA structures has been suggested in chromosomal looping this was not tested directly. Here, to test causal function, an array of G4s, or control sequence that does not form G4s, were inserted within chromatin in cells. In vivo G4 formation of the inserted G4 sequence array, and not the control sequence, was confirmed using G4-selective antibody. Compared to the control insert, we observed a remarkable increase in the number of 3D chromatin looping interactions from the inserted G4 array. This was evident within the immediate topologically associated domain (TAD) and throughout the genome. Locally, recruitment of enhancer histone marks and the transcriptional coactivator p300/Acetylated-p300 increased in the G4-array, but not in the control insertion. Resulting promoter-enhancer interactions and gene activation were clear up to 5 Mb away from the insertion site. Together, these show the causal role of G4s in enhancer function and long-range chromatin interactions. Mechanisms of 3D topology are primarily based on DNA-bound architectural proteins that induce/stabilize long-range interactions. Involvement of the underlying intrinsic DNA sequence/structure in 3D looping shown here therefore throws new light on how long-range chromosomal interactions might be induced or maintained.