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. Invivo 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. Wiegreffe etal. 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.
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