title: 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.
authors: Department of Neurology, University of California, 1550 Fourth Street, San Francisco, CA 94158, USA.
authors: Konstantinos
authors: K
authors: Zarbalis
authors: Julie A
authors: JA
authors: Siegenthaler
authors: Youngshik
authors: Y
authors: Choe
authors: Scott R
authors: SR
authors: May
authors: Andrew S
authors: AS
authors: Peterson
authors: Samuel J
authors: SJ
authors: Pleasure
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000254:growth & development* / Q000473:pathology; D005038:Ethylnitrosourea; D051858:Forkhead Transcription Factors / Q000235:genetics*; D008578:Meninges / Q000166:cytology* / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000473:pathology; D017354:Point Mutation
chemical_list: D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D005038:Ethylnitrosourea
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