1. Developmental Biology
  2. Evolutionary Biology
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An ancient yet flexible cis-regulatory architecture allows localized Hedgehog tuning by patched/Ptch1

  1. David S Lorberbaum
  2. Andrea I Ramos
  3. Kevin A Peterson
  4. Brandon S Carpenter
  5. David S Parker
  6. Sandip De
  7. Lauren E Hillers
  8. Victoria M Blake
  9. Yuichi Nishi
  10. Matthew R McFarlane
  11. Ason CY Chiang
  12. Judith A Kassis
  13. Benjamin L Allen
  14. Andrew P McMahon
  15. Scott Barolo  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. Harvard University, United States
  3. National Institutes of Health, United States
  4. University of Southern California Keck School of Medicine, United States
  5. Keck School of Medicine of the University of Southern California, United States
Research Article
  • Cited 24
  • Views 2,726
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Cite this article as: eLife 2016;5:e13550 doi: 10.7554/eLife.13550

Abstract

The Hedgehog signaling pathway is part of the ancient developmental-evolutionary animal toolkit. Frequently co-opted to pattern new structures, the pathway is conserved among eumetazoans yet flexible and pleiotropic in its effects. The Hedgehog receptor, Patched, is transcriptionally activated by Hedgehog, providing essential negative feedback in all tissues. Our locus-wide dissections of the cis-regulatory landscapes of fly patched and mouse Ptch1 reveal abundant, diverse enhancers with stage- and tissue-specific expression patterns. The seemingly simple, constitutive Hedgehog response of patched/Ptch1 is driven by a complex regulatory architecture, with batteries of context-specific enhancers engaged in promoter-specific interactions to tune signaling individually in each tissue, without disturbing patterning elsewhere. This structure-one of the oldest cis-regulatory features discovered in animal genomes-explains how patched/Ptch1 can drive dramatic adaptations in animal morphology while maintaining its essential core function. It may also suggest a general model for the evolutionary flexibility of conserved regulators and pathways.

Article and author information

Author details

  1. David S Lorberbaum

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Andrea I Ramos

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kevin A Peterson

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Brandon S Carpenter

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. David S Parker

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sandip De

    Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lauren E Hillers

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Victoria M Blake

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuichi Nishi

    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California Keck School of Medicine, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Matthew R McFarlane

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ason CY Chiang

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Judith A Kassis

    Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Benjamin L Allen

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Andrew P McMahon

    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad-CIRM Center for Regenerative Medicine and Stem Biology, Keck School of Medicine of the University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Scott Barolo

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
    For correspondence
    sbarolo@umich.edu
    Competing interests
    The authors declare that no competing interests exist.

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, and with the institutional animal care protocols of Harvard University and The Jackson Laboratories, where the animal experimentation was performed.Animal husbandry and all experiments were performed in accordance with the National Institute of Health guidelines and the Institutional Animal Care and Use Committee of the University of Southern California (protocol #11867).

Reviewing Editor

  1. Janet Rossant, University of Toronto, Canada

Publication history

  1. Received: December 4, 2015
  2. Accepted: May 3, 2016
  3. Accepted Manuscript published: May 5, 2016 (version 1)
  4. Version of Record published: May 31, 2016 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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