Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum
Ilan Gobius,
Laura Morcom,
Rodrigo Suárez,
Jens Bunt,
Polina Bukshpun,
William Reardon,
William B. Dobyns,
John L.R. Rubenstein,
A. James Barkovich,
Elliott H. Sherr,
Linda J. Richards
Affiliations
Ilan Gobius
Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
Laura Morcom
Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
Rodrigo Suárez
Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
Jens Bunt
Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
Polina Bukshpun
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
William Reardon
National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland
William B. Dobyns
Center for Integrative Brain Research, Seattle Children’s Research Institute, University of Washington, Seattle, WA 98101, USA
John L.R. Rubenstein
Department of Psychiatry, Neuroscience Program and Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158, USA
A. James Barkovich
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143-0628, USA
Elliott H. Sherr
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Linda J. Richards
Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia
The corpus callosum is the major axon tract that connects and integrates neural activity between the two cerebral hemispheres. Although ∼1:4,000 children are born with developmental absence of the corpus callosum, the primary etiology of this condition remains unknown. Here, we demonstrate that midline crossing of callosal axons is dependent upon the prior remodeling and degradation of the intervening interhemispheric fissure. This remodeling event is initiated by astroglia on either side of the interhemispheric fissure, which intercalate with one another and degrade the intervening leptomeninges. Callosal axons then preferentially extend over these specialized astroglial cells to cross the midline. A key regulatory step in interhemispheric remodeling is the differentiation of these astroglia from radial glia, which is initiated by Fgf8 signaling to downstream Nfi transcription factors. Crucially, our findings from human neuroimaging studies reveal that developmental defects in interhemispheric remodeling are likely to be a primary etiology underlying human callosal agenesis.
