1. Developmental Biology
  2. Neuroscience
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DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation

  1. Laura Morcom
  2. Ilan Gobius
  3. Ashley PL Marsh
  4. Rodrigo Suárez
  5. Jonathan WC Lim
  6. Caitlin Bridges
  7. Yunan Ye
  8. Laura R Fenlon
  9. Yvrick Zagar
  10. Amelia M Douglass
  11. Amber-Lee Donahoo
  12. Thomas Fothergill
  13. Samreen Shaikh
  14. Peter Kozulin
  15. Timothy J Edwards
  16. Helen M Cooper
  17. IRC5 Consortium
  18. Elliott H Sherr
  19. Alain Chédotal
  20. Richard J Leventer
  21. Paul J Lockhart
  22. Linda J Richards  Is a corresponding author
  1. The University of Queensland, Australia
  2. Murdoch Childrens Research Institute, Australia
  3. Institut de la Vision, France
  4. University of California, San Francisco, United States
  5. Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, France
  6. Murdoch Childrens Research Institute and Royal Childrens Hospital, Australia
Research Article
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Cite this article as: eLife 2021;10:e61769 doi: 10.7554/eLife.61769
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Abstract

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures that contain numerical data.

Article and author information

Author details

  1. Laura Morcom

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Ilan Gobius

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Ashley PL Marsh

    Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6049-6931
  4. Rodrigo Suárez

    Queensland Brain Institute, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Jonathan WC Lim

    Queensland Brain Institute, School of Biomedical Sciences, The University of Queensland, St Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5074-6359
  6. Caitlin Bridges

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Yunan Ye

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Laura R Fenlon

    Queensland Brain Institute, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Yvrick Zagar

    Department of Development, Institut de la Vision, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Amelia M Douglass

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5398-6473
  11. Amber-Lee Donahoo

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Thomas Fothergill

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Samreen Shaikh

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Peter Kozulin

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7872-9884
  15. Timothy J Edwards

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  16. Helen M Cooper

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  17. IRC5 Consortium

  18. Elliott H Sherr

    Departments of Neurology and Pediatrics, Institute of Human Genetics and Weill Institute of Neurosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Alain Chédotal

    Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7577-3794
  20. Richard J Leventer

    Bruce Lefroy Centre for Genetic Health Research and Department of Neurology, Murdoch Childrens Research Institute and Royal Childrens Hospital, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  21. Paul J Lockhart

    Genetics, Murdoch Childrens Research Institute, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2531-8413
  22. Linda J Richards

    Queensland Brain Institute, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
    For correspondence
    richards@uq.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7590-7390

Funding

National Health and Medical Research Council (GNT456027)

  • Linda J Richards

Queensland Brain Institute (Top-Up scholarship)

  • Amber-Lee Donahoo

University of Queensland (UQ development fellowship)

  • Laura R Fenlon

Murdoch Children's Research Institute (Melbourne Children's Clinician Scientist fellowship)

  • Richard J Leventer

National Health and Medical Research Council (Principal research fellowship,GNT1120615)

  • Linda J Richards

Department of Education, Skills and Employment (Australian Postgraduate Award)

  • Amber-Lee Donahoo

National Health and Medical Research Council (GNT631466)

  • Linda J Richards

National Health and Medical Research Council (GNT1048849)

  • Linda J Richards

National Health and Medical Research Council (GNT1126153)

  • Linda J Richards

National Health and Medical Research Council (GNT1059666)

  • Richard J Leventer
  • Paul J Lockhart

National Institutes of Health (5R01NS058721)

  • Elliott H Sherr
  • Linda J Richards

Australian Research Council (DE160101394)

  • Rodrigo Suárez

Department of Education, Skills and Employment Australia (Research training program scholarship)

  • Ashley PL Marsh

National Health and Medical Research Council (Early career research fellowship,APP1156820)

  • Ashley PL Marsh

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

Ethics

Animal experimentation: Prior approval for all breeding and experiments was obtained from the University of Queensland Animal Ethics Committee and was conducted in accordance with the Australian code for the care and use of animals for scientific purposes. The protocol, experiments and animal numbers were approved under the following project approval numbers: QBI/305/17, QBI/311/14 NHMRC (NF), QBI/356/17, QBI/306/17, and QBI/240/14/MDF (NF)).

Human subjects: Ethics for human experimentation was acquired by local ethics committees at TheUniversity of Queensland (Australia), the Royal Children's hospital (Australia), andUCSF Benioff Children's Hospital (USA). The research was carried out in accordance with the provisions contained in the National Statement on Ethical Conduct in Human Research (USA) under IRB number 10-01008 and with the regulations governing experimentation on humans (Australia), under the following human ethics approvals: HEU 2007/163 (previously 2006000899), HEU 2014000535, HEU 2015001306.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Publication history

  1. Received: August 4, 2020
  2. Accepted: April 18, 2021
  3. Accepted Manuscript published: April 19, 2021 (version 1)

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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