Meningeal Bmps Regulate Cortical Layer Formation.

Neuronal connectivity in the cortex is determined by the laminar positioning of neurons. An important determinant of laminar positioning is likely to be the control of leading process behavior during migration, maintaining their tips directed toward the pia. In this study, we provide evidence that pial bone morphogenetic protein (Bmp) signaling regulates cortical neuronal migration during cortical layer formation. Specific disruption of pial Bmp ligands impaired the positioning of early-born neurons in the deep layer; further, cell-autonomous inhibition of Smad4, a core nuclear factor mediating Bmp signaling, in the cortical radial glial cells or postmitotic cortical neurons also produced neuronal migration defects that blurred the cortical layers. We found that leading processes were abnormal and that this was accompanied by excess dephosphorylated cofilin-1, an actin-severing protein, in Smad4 mutant neurons. This suggested that regulation of cofilin-1 might transduce Bmp signaling in the 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 layer, similar to the Smad4 mutant neurons. Expression of a phosphomimetic variant of cofilin-1 in the Smad4 mutant neurons rescued the migration defects. This suggests that cofilin-1 activity 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.