Asymmetric divisions of radial glial progenitors produce self-renewing radial glia and differentiating cells simultaneously in the ventricular zone (VZ) of the developing neocortex. While differentiating cells leave the VZ to constitute the future neocortex, renewing radial glial progenitors stay in the VZ for subsequent divisions. The differential behaviour of progenitors and their differentiating progeny is essential for neocortical development; however, the mechanisms that ensure these behavioural differences are unclear. Here we show that asymmetric centrosome inheritance regulates the differential behaviour of renewing progenitors and their differentiating progeny. Centrosome duplication in dividing radial glial progenitors generates a pair of centrosomes with differently aged mother centrioles. During peak phases of neurogenesis, the centrosome retaining the old mother centriole stays in the VZ and is preferentially inherited by radial glial progenitors, whereas the centrosome containing the new mother centriole mostly leaves the VZ and is largely associated with differentiating cells. Removal of Ninein, a mature centriole-specific protein, disrupts the asymmetric segregation and inheritance of the centrosome and causes premature depletion of progenitors from the VZ. These results suggest that preferential inheritance of the centrosome with the mature older mother centriole is required for maintaining radial glial progenitors in the developing mammalian neocortex.

Radial glial progenitor cells (RGPCs), have been long known to exhibit a striking form of bidirectional nuclear migration. The purpose and underlying mechanism for this unusual cell cycle-dependent “interkinetic” nuclear migration has remained poorly understood. We investigated the basis for this behavior by live imaging of nuclei, centrosomes, and microtubules in embryonic rat brain slices, coupled with blebbistatin and RNAi. We observed nuclei to migrate independent of centrosomes and unidirectionally away from or toward the ventricular surface along microtubules, which we found to be uniformly oriented from the ventricular to the pial surfaces of the brain. Cytoplasmic dynein RNAi specifically inhibited apically-directed nuclear movement. An RNAi screen for kinesin genes identified KIF1A, a member of the kinesin 3 family, as the motor for basally-directed nuclear movement. These observations provide the first direct evidence for a role for kinesins in nuclear migration and neurogenesis, and suggest that a novel cell cycle-dependent switch between distinct microtubule motors drives INM.