title: Astroglial-Mediated Remodeling of the Interhemispheric Midline Is Required for the Formation of the Corpus Callosum.
abstract: 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.
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia. Electronic address: ilan.gobius@gmail.com.
authors.forename: Ilan
authors.initials: I
authors.lastname: Gobius
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Morcom
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Suárez
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Jens
authors.initials: J
authors.lastname: Bunt
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Bukshpun
authors.affiliation: National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.
authors.forename: William
authors.initials: W
authors.lastname: Reardon
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington, Seattle, WA 98101, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Department of Psychiatry, Neuroscience Program and Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143-0628, USA.
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia; The School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD 4072, Australia. Electronic address: richards@uq.edu.au.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Richards
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation; D054022:Cerebrum / Q000196:embryology*; D003337:Corpus Callosum / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D006801:Humans; D051379:Mice; D038081:Organogenesis; D010641:Phenotype; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8
keywords: Fgf8; Nfia; Nfib; astrocyte; callosal agenesis; interhemispheric fissure