Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development
- 28 August 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 104 (35), 14002-14007
- https://doi.org/10.1073/pnas.0702618104
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.Keywords
This publication has 38 references indexed in Scilit:
- Schizophrenia in an adult with 6p25 deletion syndromeAmerican Journal of Medical Genetics Part A, 2006
- Foxc1 integrates Fgf and Bmp signalling independently of twist or noggin during calvarial bone developmentDevelopmental Dynamics, 2005
- Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndromeAmerican Journal of Medical Genetics Part A, 2005
- Subtelomeric 6p deletion: Clinical, FISH, and array CGH characterization of two casesAmerican Journal of Medical Genetics Part A, 2004
- A Focused and Efficient Genetic Screening Strategy in the Mouse: Identification of Mutations That Disrupt Cortical DevelopmentPLoS Biology, 2004
- Beyond Laminar Fate: Toward a Molecular Classification of Cortical Projection/Pyramidal NeuronsDevelopmental Neuroscience, 2003
- The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesisGenes & Development, 2001
- Analyses of the Effects That Disease-Causing Missense Mutations Have on the Structure and Function of the Winged-Helix Protein FOXC1American Journal of Human Genetics, 2001
- A Spectrum of FOXC1 Mutations Suggests Gene Dosage as a Mechanism for Developmental Defects of the Anterior Chamber of the EyeAmerican Journal of Human Genetics, 2001
- Meningeal cells organize the superficial glia limitans of the cerebellum and produce components of both the interstitial matrix and the basement membraneJournal of Neurocytology, 1994