Recent studies from our laboratory showed that the meninges are an important source of signals during cortical development regulating several important events in the forming cortex. We showed that the meninges produces retinoic acid that regulates neural stem cell behavior, SDF1 that regulates neuronal migration and Bmps that regulate axon guidance during cortical development. In this talk I will review this area and also discuss our recent studies showing that Bmps produced by the meninges are important regulators of cortical lamination.

Neuronal connectivity in the cortex is determined in part by the laminar positioning of excitatory projection neurons. The decision to stop migrating is controlled ultimately by the leading processes of the migrating neurons. In this study, we show that pial bone morphogenetic protein (Bmp) signaling regulates cortical neuronal migration during embryonic development. Specific inhibition of pial Bmp ligands impaired positioning of early born neurons in the deep layers and cell-autonomous deletion of Smad4, a core nuclear factor mediating Bmp signaling, in the cortical radial glial cells or postmitotic cortical neurons also showed neuronal migration defects with loss of failure of proper cortical lamination. The leading processes of Smad4 mutant neurons had aberrant projection accompanied by loss of phosporylated cofilin-1, an actin severing protein. This indicates that the cofilin phosphorylation cycle may transduce Bmp signaling in migrating neurons. Ectopic expression of a phosphorylation-defective form of cofilin-1 in the late born wild-type neurons led them to stall in the deep layers similar to our observations in the Smad4 mutant neurons. Rescue the phosphorylated status of cofilin-1 by the expression of a variant of cofilin-1 mimicking phosphorylation in the Smad4 mutant neurons rescued the migration defects of these neurons suggesting that activities of cofilin-1 underlies Bmp-mediated cortical neuronal migration. This study shows that cofilin-1 mediates pial Bmp signaling during the positioning of cortical neurons and the formation of cortical layers.