Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c

During neocortical development, neurons undergo polarization, oriented migration, and layer-type-specific differentiation. The transcriptional programs underlying these processes are not completely understood. Here, we show that the transcription factor Bcl11a regulates polarity and migration of upper layer neurons. Bcl11a-deficient late-born neurons fail to correctly switch from multipolar to bipolar morphology, resulting in impaired radial migration. We show that the expression of Sema3c is increased in migrating Bcl11a-deficient neurons and that Bcl11a is a direct negative regulator of Sema3c transcription. In vivo gain-of-function and rescue experiments demonstrate that Sema3c is a major downstream effector of Bcl11a required for the cell polarity switch and for the migration of upper layer neurons. Our data uncover a novel Bcl11a/Sema3c-dependent regulatory pathway used by migrating cortical neurons. •Bcl11a controls cell polarity and radial migration of upper layer cortical neurons•Sema3c is a major downstream effector of Bcl11a in migrating cortical neurons•Morphogenesis and survival of postmigratory upper layer neurons depend on Bcl11a•Deletion of Bcl11a in mice results in hypoplasia of superficial neocortex Wiegreffe et al. discover a novel Bcl11a/Sema3c-dependent regulatory pathway that controls polarization and radial migration of late-born upper layer cortical projection neurons. Deletion of Bcl11a in mice ultimately results in severe hypoplasia of upper neocortical layers.