Primary cellular meningeal defects cause neocortical dysplasia and dyslamination
Article first published online: 25 OCT 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 68, Issue 4, pages 454–464, October 2010
How to Cite
Hecht, J. H., Siegenthaler, J. A., Patterson, K. P. and Pleasure, S. J. (2010), Primary cellular meningeal defects cause neocortical dysplasia and dyslamination. Ann Neurol., 68: 454–464. doi: 10.1002/ana.22103
- Issue published online: 25 OCT 2010
- Article first published online: 25 OCT 2010
- Manuscript Accepted: 20 MAY 2010
- Manuscript Revised: 14 MAY 2010
- Manuscript Received: 24 FEB 2010
Cortical malformations are important causes of neurological morbidity, but in many cases their etiology is poorly understood. Mice with Foxc1 mutations have cellular defects in meningeal development. We use hypomorphic and null alleles of Foxc1 to study the effect of meningeal defects on neocortical organization.
Embryos with loss of Foxc1 activity were generated using the hypomorphic Foxc1hith allele and the null Foxc1lacZ allele. Immunohistologic analysis was used to assess cerebral basement membrane integrity, marginal zone heterotopia formation, neuronal overmigration, meningeal defects, and changes in basement membrane composition. Dysplasia severity was quantified using 2 measures.
Cortical dysplasia resembling cobblestone cortex, with basement membrane breakdown and lamination defects, is seen in Foxc1 mutants. As Foxc1 activity was reduced, abnormalities in basement membrane integrity, heterotopia formation, neuronal overmigration, and meningeal development appeared earlier in gestation and were more severe. Surprisingly, the basement membrane appeared intact at early stages of development in the face of severe deficits in meningeal development. Prominent defects in basement membrane integrity appeared as development proceeded. Molecular analysis of basement membrane laminin subunits demonstrated that loss of the meninges led to changes in basement membrane composition.
Cortical dysplasia can be caused by cellular defects in the meninges. The meninges are not required for basement membrane establishment but are needed for remodeling as the brain expands. Specific changes in basement membrane composition may contribute to subsequent breakdown. Our study raises the possibility that primary meningeal defects may cortical dysplasia in some cases. Ann Neurol 2010;68:454–464