Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development

Abstract

We report the identification of a hypomorphic mouse allele for Foxc1 (Foxc1 hith ) that survives into adulthood revealing previously unknown roles for Foxc1 in development of the skull and cerebral cortex. This line of mice was recovered in a forward genetic screen using ENU mutagenesis to identify mutants with cortical defects. In the hith allele a missense mutation substitutes a Leu for a conserved Phe at amino acid 107, leading to destabilization of the protein without substantially altering transcriptional activity. Embryonic and postnatal histological analyses indicate that diminished Foxc1 protein expression in all three layers of meningeal cells in Foxc1 hith/hith mice contributes to the cortical and skull defects in mutant mice and that the prominent phenotypes appear as the meninges differentiate into pia, arachnoid, and dura. Careful analysis of the cortical phenotypes shows that Foxc1 hith/hith mice display detachment of radial glial endfeet, marginal zone heterotopias, and cortical dyslamination. These abnormalities have some features resembling defects in type 2 (cobblestone) lissencephaly or congenital muscular dystrophies but appear later in corticogenesis because of the delay in breakdown of the basement membrane. Our data reveal that the meninges regulate the development of the skull and cerebral cortex by controlling aspects of the formation of these neighboring structures. Furthermore, we provide evidence that defects in meningeal differentiation can lead to severe cortical dysplasia.genetic screen ͉ meninges ͉ migration

Postnatal Development of the Central Nervous System: Anomalies in the Formation of Cerebellum Fissures

“…glial cells lost their footing to the pial surface and retracted wherever the pial basement membrane was ruptured (Halfter et al, 2002;Zerbalis et al, 2007).…”

“…The involvement of the meninges in the development of the perturbed foliation pattern has been claimed (Stoughton et al, 1978;Lyon et al, 1993;Necchi et al, 2000;Zerbalis et al, 2007).…”

Abnormal development of the human cerebral cortex

“…First, in several mutations associated with cortical dysplasia the pial basement membrane appears to develop normally; breaches develop later (Blackshear et al 1997;Hu et al 2007;Li et al 2008), suggesting that defects arise as a result of instability of the basement membrane during remodelling and brain growth. Secondly, it appears that the basement membrane per se may influence cortical development (Zarbalis et al 2007;Radakovits et al 2009;Siegenthaler et al 2009). Foxc1 is a protein expressed in all three meningeal layers; homozygous mouse mutants show normal early formation of the pial basement membrane, which later develops defects associated with detached radial glial end feet leading to disorganization of cortical neurons in the marginal zone (Zarbalis et al 2007).…”

“…Secondly, it appears that the basement membrane per se may influence cortical development (Zarbalis et al 2007;Radakovits et al 2009;Siegenthaler et al 2009). Foxc1 is a protein expressed in all three meningeal layers; homozygous mouse mutants show normal early formation of the pial basement membrane, which later develops defects associated with detached radial glial end feet leading to disorganization of cortical neurons in the marginal zone (Zarbalis et al 2007). However, in this model there does not appear to be the extensive overmigration characteristic of cobblestone lissencephaly, instead the dysplasia is intracortical.…”

“…A third pattern of cortical malformation is associated with defective pial expression of Foxc1 protein, a protein normally expressed in all layers of the meninges (Zarbalis et al 2007). In this model, initial cortical development is also normal, but later, at E18.5, basement membrane defects appear and there is disorganization of glial end feet.…”