Functions of the centrosome in embryonic neurogenesis

The architecture of the mammalian brain is formed through a series of coordinated events, including cell proliferation, cell fate determination, migration and layering. The centrosome is crucial for many of these processes during embryonic brain development. Disruption of the functions of centrosome-associated proteins leads to severe neurological disorders, ranging from lissencephaly, microcephaly to psychiatric diseases. In order to understand the mechanisms underlying centrosomal regulation of cortical development, we investigated functions of two centrosome-related proteins, Hook2 and Hook3, in embryonic cortical development. Although the two proteins have high similarity in their sequences, they exhibit distinct subcellular localizations and play different roles in cortical development. Hook3 localizes to pericentriolar satellites through interaction with Pericentriolar Material 1 (PCM1), and is required for the dynamic assembly of centrosomal proteins and for microtubule anchorage to the centrosome. Silencing Hook3 or PCM1 by RNA interference, or disruption of the Hook3-PCM1 interaction, impairs interkinetic nuclear migration (INM) and leads to premature neuronal differentiation and depletion of neural progenitor pool in the developing mouse neocortex. These results underscore the importance of dynamic centrosomal assembly in INM and its requirement for the proper regulation of neurogenesis. In contrast, Hook2 localizes to the centrosome in close proximity to the centriole. Hook2 interacts with centrobin, a protein specifically associated with the daughter centriole and required for centrosome duplication. Similar to the phenotype of centrobin loss-of-function, silencing Hook2 by RNA interference impairs centrosome duplication, resulting in abnormal mitotic spindles and early G1 phase arrest in interphase cells. In vivo knockdown of Hook2 retains neural progenitors in the apical side of the ventricular zone, and prevents neuronal differentiation. We propose that Hook2 controls centrosome duplication and is thus required for normal cell cycle progression in neural progenitors. Hook2 may also be required for the formation of neural cilia, which may play important roles in signal transduction and cell fate determination.