1. Neuroscience
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Downregulation of ribosome biogenesis during early forebrain development

Research Article
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Cite this article as: eLife 2018;7:e36998 doi: 10.7554/eLife.36998
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Abstract

Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids. Notably, c-MYC expression and mTOR pathway signaling were also decreased at E10.5, providing a potential driver for the effects on ribosome biogenesis and protein synthesis. Interference with c-MYC at E8.5 prematurely decreased ribosome biogenesis, while persistent c-MYC expression in cortical progenitors increased transcription of protein biosynthetic machinery and enhanced ribosome biogenesis, as well as enhanced progenitor proliferation leading to subsequent macrocephaly. These findings indicate large, coordinated changes in molecular machinery of forebrain precursors during early brain development.

Data availability

Sequencing data have been deposited in GEO under accession number GSE100421.

The following data sets were generated

Article and author information

Author details

  1. Kevin F Chau

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Morgan L Shannon

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryann M Fame

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8244-2624
  4. Erin Fonseca

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hillary Mullan

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Matthew B Johnson

    Division of Genetics, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6909-5712
  7. Anoop K Sendamarai

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mark W Springel

    Department of Pathology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Benoit Laurent

    Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Maria K Lehtinen

    Department of Pathology, Boston Children's Hospital, Boston, United States
    For correspondence
    maria.lehtinen@childrens.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7243-2967

Funding

National Science Foundation (Graduate Research Fellowship)

  • Kevin F Chau

National Institutes of Health (R01 NS088566)

  • Maria K Lehtinen

Pediatric Hydrocephalus Foundation (Research grant)

  • Maria K Lehtinen

Simons Foundation (SFARI Pilot Grant)

  • Maria K Lehtinen

New York Stem Cell Foundation (Robertson Investigator)

  • Maria K Lehtinen

National Institutes of Health (NIH T32 HL110852)

  • Kevin F Chau

National Institutes of Health (NIH T32 HL110852)

  • Ryann M Fame

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 experimentation was carried out under protocols approved by the IACUC of Boston Children's Hospital (protocol number 17-10-3547R).

Reviewing Editor

  1. Marianne Bronner, California Institute of Technology, United States

Publication history

  1. Received: March 28, 2018
  2. Accepted: May 9, 2018
  3. Accepted Manuscript published: May 10, 2018 (version 1)
  4. Version of Record published: June 1, 2018 (version 2)

Copyright

© 2018, Chau 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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