1. Developmental Biology
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A chemical screen in zebrafish embryonic cells establishes that Akt activation is required for neural crest development

  1. Christie Ciarlo
  2. Charles K Kaufman
  3. Beste Kinikoglu
  4. Jonathan Michael
  5. Song Yang
  6. Christopher D′Amato
  7. Sasja Blokzijl-Franke
  8. Jeroen den Hertog
  9. Thorsten M Schlaeger
  10. Yi Zhou
  11. Eric Liao
  12. Leonard I Zon  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Washington University School of Medicine, United States
  3. Harvard Medical School, United States
  4. Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Center Utrecht, Netherlands
Research Article
  • Cited 9
  • Views 2,377
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Cite this article as: eLife 2017;6:e29145 doi: 10.7554/eLife.29145

Abstract

The neural crest is a dynamic progenitor cell population that arises at the border of neural and non-neural ectoderm. The inductive roles of FGF, Wnt, and BMP at the neural plate border are well established, but the signals required for subsequent neural crest development remain poorly characterized. Here, we conducted a screen in primary zebrafish embryo cultures for chemicals that disrupt neural crest development, as read out by crestin:EGFP expression. We found that the natural product caffeic acid phenethyl ester (CAPE) disrupts neural crest gene expression, migration, and melanocytic differentiation by reducing Sox10 activity. CAPE inhibits FGF-stimulated PI3K/Akt signaling, and neural crest defects in CAPE-treated embryos are suppressed by constitutively active Akt1. Inhibition of Akt activity by constitutively active PTEN similarly decreases crestin expression and Sox10 activity. Our study has identified Akt as a novel intracellular pathway required for neural crest differentiation.

Article and author information

Author details

  1. Christie Ciarlo

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2876-2432
  2. Charles K Kaufman

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  3. Beste Kinikoglu

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. Jonathan Michael

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  5. Song Yang

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  6. Christopher D′Amato

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  7. Sasja Blokzijl-Franke

    Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  8. Jeroen den Hertog

    Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  9. Thorsten M Schlaeger

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  10. Yi Zhou

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  11. Eric Liao

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  12. Leonard I Zon

    Stem Cell Program and Hematology/Oncology, Boston Children's Hospital, Boston, United States
    For correspondence
    zon@enders.tch.harvard.edu
    Competing interests
    Leonard I Zon, L.I.Z. is a founder and stock holder of Fate Therapeutics, Marauder Therapeutics, and Scholar Rock..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0860-926X

Funding

National Institutes of Health (F31CA180313)

  • Christie Ciarlo

Melanoma Research Alliance

  • Leonard I Zon

Lawrence Ellison Foundation

  • Leonard I Zon

Howard Hughes Medical Institute

  • Leonard I Zon

National Institutes of Health (R01CA103846)

  • Leonard I Zon

National Institutes of Health (RO3DE024490)

  • Eric Liao

National Institutes of Health (K08AR061071)

  • Charles K Kaufman

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

Ethics

Animal experimentation: Zebrafish were maintained under standard protocols approved by the Boston Children's Hospital (BCH) Institutional Animal Care and Use Committee (IACUC) (protocol # 14-10-2789R).

Reviewing Editor

  1. Tanya T Whitfield, University of Sheffield, United Kingdom

Publication history

  1. Received: May 31, 2017
  2. Accepted: August 8, 2017
  3. Accepted Manuscript published: August 23, 2017 (version 1)
  4. Version of Record published: September 14, 2017 (version 2)

Copyright

© 2017, Ciarlo 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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