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SummaryExtrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal formation. Foxc1 dosage and loss of meninges correlated with a dramatic reduction in both neuron and intermediate progenitor production and elongation of the neuroepithelium. Several types of experiments demonstrate that retinoic acid (RA) is the key component of this secreted activity. In addition, Rdh10- and Raldh2-expressing cells in the dorsal meninges were either reduced or absent in the Foxc1 mutants, and Rdh10 mutants had a cortical phenotype similar to the Foxc1 null mutants. Lastly, in utero RA treatment rescued the cortical phenotype in Foxc1 mutants. These results establish RA as a potent, meningeal-derived cue required for successful corticogenesis.

RACK1 is a multifunctional scaffolding protein known to be involved in the regulation of various signaling cascades in the central nervous system (CNS). In order to gain insight into the neurological functions of RACK1, we examined the expression of RACK1 mRNA and protein during gestation and in the adult mouse brain. Several expression patterns were observed. At embryonic day 11.5 (E11.5), RACK1 is expressed in a high-dorsal to low-ventral gradient throughout the brain. At E13.5, RACK1 is most abundant in the telencephalon. In the developing cortical primordium, RACK1 protein is expressed in a high-rostromidline to low-caudolateral gradient that appears to be regulated post-transcriptionally. At E18.5, RACK1 is expressed most abundantly in layers 1–4 of the cortex, striatum, hippocampus, dentate gyrus and specific thalamic nuclei. In the adult mouse, RACK1 is ubiquitously expressed in neuronal perikarya in most brain regions, with relatively higher levels in hippocampus, olfactory bulb, cortex and cerebellum. Subcellular staining was detected mainly in the cell bodies and extending into dendrites, whereas RACK1 was not present significantly in axonal fibers or nuclei. We also determined brain regions in which RACK1 interacts with one of its binding partners, the βII isoform of protein kinase C (βIIPKC). We found that βIIPKC had a much more restricted expression pattern than RACK1 and overlapped with the scaffolding protein only in certain regions, including the CA1 area of the hippocampus, cerebellum and striatum. Our results suggest an important role for RACK1 during CNS development and support multiple functions of the protein in the adult brain.

Sonic Hedgehog (Shh) signals are transduced into nuclear ratios of Gli transcriptional activator versus repressor. The initial part of this process is accomplished by Shh acting through Patched (Ptc) to regulate Smoothened (Smo) activity. The mechanisms by which Ptc regulates Smo, and Smo activity is transduced to processing of Gli proteins remain unclear. Recently, a forward genetic approach in mice identified a role for intraflagellar transport (IFT) genes in Shh signal transduction, downstream of Patched (Ptc) and Rab23. Here, we show that the retrograde motor for IFT is required in the mouse for the phenotypic expression of both Gli activator and repressor function and for effective proteolytic processing of Gli3. Furthermore, we show that the localization of Smo to primary cilia is disrupted in mutants. These data indicate that primary cilia act as specialized signal transduction organelles required for coupling Smo activity to the biochemical processing of Gli3 protein.