The meninges were traditionally considered to be a protective covering of the CNS, with roles limited to cerebrospinal fluid and blood circulation. In recent years several important additional signaling roles of the meninges have been established. The meninges produce Cxcl12, which guides neuronal migration 
and BMPs, which regulate the formation of the corpus callosum 
. The meninges also synthesize RA, which regulates the onset of asymmetric divisions in the developing cortical neuroepithelium 
. During development cortical neurons are born in a gradient from ventral to dorsal and rostral to caudal. Meningeal fibroblasts, derived from the neural crest, migrate in a ventral to dorsal wave from E10.5 and surround the developing forebrain and begin expressing RA synthesizing enzymes beginning at E12 
. The migration of the meningeal fibroblasts and the initiation of expression of the RA synthesizing enzymes are coincident with the transition from symmetric proliferative divisions to asymmetric neurogenic divisions across the neurogenic gradient. The meninges are positioned and synthesize RA in a manner to temporally and spatially influence the regulation of radial glia, including controlling cortical neurogenesis and previous studies from our laboratory using Foxc1-mutant animals support this hypothesis 
. This study supports the hypothesis that meningeal mediated RA signaling in radial glia involves the transcription factor CoupTFI.
The nuclear orphan receptor CoupTFI is a known modulator of retinoid responses in other systems 
, CoupTFI regulates neuronal differentiation 
, and D6-CoupTFI mice display elevated cortical RA signaling 
. Our studies demonstrate a requirement for CoupTFI to allow RA mediated rescue of neurogenesis in Foxc1-mutants. We also found that overexpression of CoupTFI partially rescues the cortical phenotypes in Foxc1-mutants. Thus, our studies provide evidence that that CoupTFI interacts with RA signaling in the developing cortex.
A partial rescue of the ventricular zone length and the numbers of Pax6+
radial glia cells was observed in CoupTFI−/−
mutants following RA treatment, whereas, Tbr2 and neuron cell numbers were not rescued. This suggests that RA regulation of symmetric proliferation (i.e. the expansion of the radial glia population) requires other signaling interactions as well. However, the RA mediated regulation of the production of intermediate progenitor cells and neurons, which proceed via asymmetric divisions, is dependent on CoupTFI. Consistent with this hypothesis, our overexpression studies (), in which ventricular zone length and neurogenesis are rescued but the number of Pax6+
radial glia is further decreased, suggest that CoupTFI is sufficient to partially restore neurogenesis in Foxc1-mutants by promoting asymmetric neurogenic divisions at the expense of symmetric proliferative divisions. The cortical phenotype of Foxc1-mutants is evident from E12.5 and, based on expression of RA-synthesizing enzymes, meningeal RA synthesis initiates at around E12 
. In the D6-CoupTFI rescue model, CoupTFI is overexpressed in cortical progenitor cells from E10.5 
. The partial rescue observed in D6-CoupTFI;Foxc1H/L
animals may also reflect a timing issue of expression of CoupTFI under the control of the D6-promoter and the early depletion of progenitor cells in D6-CoupTFI mice.
Abnormalities in the ventral forebrain are observed in Foxc1-mutant animals. The lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE) frequently appear smoother than controls, without a visible LGE/MGE sulcus, as visible in and . Our preliminary data suggest that the LGE/MGE are specified and patterned (unpublished observations, S Harrison-Uy and S Pleasure). The structural alterations are not rescued with RA treatment or overexpression of CoupTFI in cortical progenitor cells, which suggests that this component of the Foxc-1 mutant phenotype is not RA-dependent or dependent on structural changes in the cortex. In Foxc1-mutants the meninges covering the ventral forebrain is intact and RA-synthesizing enzymes are present 
, suggesting that these changes may be independent of RA signaling and may be dependent upon a signaling pathway that is directly regulated by Foxc1.
CoupTFI interacts with the retinoid receptors, RAR and RXR family members, altering the targets of CoupTFI and RA signaling 
. Our studies indicate that CoupTFI is necessary for the RA mediated rescue of Foxc1-mutants and is sufficient to rescue, in part, the cortical phenotype of Foxc1-mutants. Our results are consistent with a model where meningeal RA signaling alters the interaction of CoupTFI and RAR/RXR in cortical progenitor cells. This would allow CoupTFI and RAR/RXR to complex with additional signaling partners and enables the modification of the transcriptional targets of CoupTFI and RAR/RXR. We hypothesize that this signaling mechanism is an important regulatory switch necessary for cortical neurogenesis.
A number of important signaling pathways control cortical development including Fgf, Wnt, BMP, and Notch 
. Studies of CoupTFI mutants identified changes in the Fgf regulated pathways, Mapk/Erk kinase and PI3 Kinase/Akt, and Wnt signaling 
. In the developing spinal cord Fgf signaling opposes RA signaling, regulating neural patterning and differentiation 
and RA signaling is known to interact with Wnt signaling 
. BMP and Notch signaling did not appear to be altered in the developing cortex of CoupTFI mutants 
, although CoupTFI has been implicated in Notch signaling during hair cell differentiation 
and BMP signaling in bone development 
. Interestingly, retinoic acid signaling has recently been shown to repress BMP signaling 
and the retinol binding protein CRBP1 is a direct target of Notch1 
. Thus, CoupTFI and RA signaling may function to coordinate some of the major signaling pathways that control cortical development.