Meningeal defects alter the tangential migration of cortical interneurons in Foxc1hith/hith mice

We studied a unique Foxc1 hypomorph mouse model (Foxc1hith/hith) with meningeal defects and impaired tangential migration of cortical interneurons. We identified a territorial correlation between meningeal defects and disruption of interneuron migration along the adjacent marginal zone in these animals, suggesting that impaired meningeal integrity might be the primary cause for the observed migration defects. Moreover, we postulate that the meningeal factor regulating tangential migration that is affected in homozygote mutants is the chemokine Cxcl12. In addition, by using chromatin immunoprecipitation analysis, we provide evidence that the Cxcl12 gene is a direct transcriptional target of Foxc1 in the meninges. Further, we observe migration defects of a lesser degree in Cajal-Retzius cells migrating within the cortical marginal zone, indicating a less important role for Cxcl12 in their migration. Finally, the developmental migration defects observed in Foxc1hith/hith mutants do not lead to obvious differences in interneuron distribution in the adult if compared to control animals.Our results suggest a critical role for the forebrain meninges to promote during development the tangential migration of cortical interneurons along the cortical marginal zone and Cxcl12 as the factor responsible for this property.The cerebral cortex's proper functioning depends on the balance between excitatory projection neurons and inhibitory interneurons. In rodents, most GABA (γ-aminobutyric acid)-producing interneurons of the cerebral cortex originate in the medial ganglionic eminence of the ventral forebrain and migrate to their cortical destinations using a tangential route [1,2]. The subcortical origin and complex migratory path of cortical interneurons differ greatly from the origin of the cortical projection neurons and their radial migratory route. Once interneurons reach the cortex they follow mostly stereotypical routes in the marginal zone (MZ) and the subventricular zone (S