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.
Bibliographical noteFunding Information:
We are grateful to Laura Fenlon and Rowan Tweedale for critical comments on the manuscript. We thank Kathryn Green for assistance with scanning electron microscopy, Nyoman Kurniawan for assistance with MR imaging, and Jonathan Lim for assistance with luciferase assays. Microscopy was performed in the Queensland Brain Institute’s Advanced Microscopy Facility. This work was supported by Australian NHMRC grants 456027 and 1048849 to L.J.R. and 631552 to L.J.R. and J.L.R.R., Australian ARC LEIF grant LE130100078, NINDS R01 NS34661 to J.L.R.R., and NIH R01 NS058721 to E.H.S., W.B.D., and L.J.R. (subcontract) from the United States. I.G. was supported by a University of Queensland Research Scholarship, L.M. is supported by an Australian Postgraduate Award, R.S. is supported by an ARC DECRA Research Fellowship, and L.J.R. is supported by an NHMRC Principal Research Fellowship.
© 2016 The Authors
- callosal agenesis
- interhemispheric fissure