DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation

  1. Laura Morcom
  2. Timothy J Edwards
  3. Eric Rider
  4. Dorothy Jones-Davis
  5. Jonathan WC Lim
  6. Kok-Siong Chen
  7. Ryan J Dean
  8. Jens Bunt
  9. Yunan Ye
  10. Ilan Gobius
  11. Rodrigo Suárez
  12. Simone Mandelstam
  13. Elliott H Sherr  Is a corresponding author
  14. Linda J Richards  Is a corresponding author
  1. The University of Queensland, Australia
  2. University of California, San Francisco, United States
  3. University of Melbourne and The Royal Childrens Hospital, Australia

Abstract

Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base-pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.

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. Timothy J Edwards

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Eric Rider

    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.
  4. Dorothy Jones-Davis

    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.
  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. Kok-Siong Chen

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Ryan J Dean

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Jens Bunt

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

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

    Queensland Brain Institute, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. 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.
  12. Simone Mandelstam

    Radiology, University of Melbourne and The Royal Childrens Hospital, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. 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
    For correspondence
    Elliott.Sherr@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
  14. 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 (GNT1048849)

  • Linda J Richards

National Health and Medical Research Council (GNT1126153)

  • Linda J Richards

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)

  • Laura Morcom
  • Jonathan WC Lim

University of Queensland (Research Scholarship)

  • Timothy J Edwards
  • Kok-Siong Chen

Queensland Brain Institute (Top-Up Scholarship)

  • Laura Morcom
  • Timothy J Edwards
  • Jonathan WC Lim

National Health and Medical Research Council (GNT1120615)

  • Linda J Richards

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/306/17, QBI/311/14 NHMRC (NF), QBI/356/17, and QBI/310/14/UQ (NF).

Human subjects: Ethics for human experimentation was acquired by local ethics committees at The University of Queensland (Australia), and carried out in accordance with the provisions contained in the National Statement on Ethical Conduct in Human Research and with the regulations governing experimentation on humans (Australia), under the following human ethics approvals: HEU 2014000535, and HEU 2015001306.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Publication history

  1. Received: July 30, 2020
  2. Accepted: May 1, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)
  4. Version of Record published: May 20, 2021 (version 2)

Copyright

© 2021, Morcom 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

  • 543
    Page views
  • 76
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

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. Laura Morcom
  2. Timothy J Edwards
  3. Eric Rider
  4. Dorothy Jones-Davis
  5. Jonathan WC Lim
  6. Kok-Siong Chen
  7. Ryan J Dean
  8. Jens Bunt
  9. Yunan Ye
  10. Ilan Gobius
  11. Rodrigo Suárez
  12. Simone Mandelstam
  13. Elliott H Sherr
  14. Linda J Richards
(2021)
DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation
eLife 10:e61618.
https://doi.org/10.7554/eLife.61618

Further reading

    1. Neuroscience
    Payel Chatterjee et al.
    Research Article

    During flight maneuvers, insects exhibit compensatory head movements which are essential for stabilizing the visual field on their retina, reducing motion blur, and supporting visual self-motion estimation. In Diptera, such head movements are mediated via visual feedback from their compound eyes that detect retinal slip, as well as rapid mechanosensory feedback from their halteres - the modified hindwings that sense the angular rates of body rotations. Because non-Dipteran insects lack halteres, it is not known if mechanosensory feedback about body rotations plays any role in their head stabilization response. Diverse non-Dipteran insects are known to rely on visual and antennal mechanosensory feedback for flight control. In hawkmoths, for instance, reduction of antennal mechanosensory feedback severely compromises their ability to control flight. Similarly, when the head movements of freely-flying moths are restricted, their flight ability is also severely impaired. The role of compensatory head movements as well as multimodal feedback in insect flight raises an interesting question: in insects that lack halteres, what sensory cues are required for head stabilization? Here, we show that in the nocturnal hawkmoth Daphnis nerii, compensatory head movements are mediated by combined visual and antennal mechanosensory feedback. We subjected tethered moths to open-loop body roll rotations under different lighting conditions, and measured their ability to maintain head angle in the presence or absence of antennal mechanosensory feedback. Our study suggests that head stabilization in moths is mediated primarily by visual feedback during roll movements at lower frequencies, whereas antennal mechanosensory feedback is required when roll occurs at higher frequency. These findings are consistent with the hypothesis that control of head angle results from a multimodal feedback loop that integrates both visual and antennal mechanosensory feedback, albeit at different latencies. At adequate light levels, visual feedback is sufficient for head stabilization primarily at low frequencies of body roll. However, under dark conditions, antennal mechanosensory feedback is essential for the control of head movements at high of body roll.

    1. Developmental Biology
    2. Neuroscience
    Ashtyn T Wiltbank et al.
    Research Article

    Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development.