DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation
- The University of Queensland, Australia
- Murdoch Childrens Research Institute, Australia
- Institut de la Vision, France
- University of California, San Francisco, United States
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, France
- Murdoch Childrens Research Institute and Royal Childrens Hospital, Australia
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
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.
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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DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation
eLife 10:e61769.
https://doi.org/10.7554/eLife.61769
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