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.
Highlights
The corpus callosum (CC) is the largest white matter tract that mediates information transfer between brain hemispheres in placental mammals
Our results suggest that diverse Corpus callosum dysgenesis (CCD) phenotypes can arise from a single genetic event that variably disrupts interhemispheric fissure (IHF) remodelling and, the amount of substrate available for CC and hippocampal commissure (HC) axons to cross the midline, and provides the first aetiology associated with partial CCD
We identified variable HC size in animals with complete CCD, suggesting that distinct subpopulations of CCD with variable HC dysgenesis may occur within the BTBR Â C57 N2 mouse (Figure 1C, D)
Summary
The corpus callosum (CC) is the largest white matter tract that mediates information transfer between brain hemispheres in placental mammals. We previously demonstrated that in order for callosal axons to cross the midline, the interhemispheric fissure (IHF) that separates the telencephalic hemispheres must be remodelled to form a permissive substrate Using the F2 generation of BTBR Â C57Bl/6J (C57) intercross, which displays variable CCD and HC dysgenesis, we previously demonstrated that a highly penetrant locus on chromosome 4 was associated with CC and HC size (Jones-Davis et al, 2013) This suggests that the degree of dysgenesis of two major telencephalic commissures may result from disruption of a single developmental process. Our results suggest that diverse CCD phenotypes can arise from a single genetic event that variably disrupts IHF remodelling and, the amount of substrate available for CC and HC axons to cross the midline, and provides the first aetiology associated with partial CCD
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