Axin Directs the Amplification and Differentiation of Intermediate Progenitors in the Developing Cerebral Cortex

•Axin increases the population of IPs and results in enhanced production of neurons•Cdk5-dependent phosphorylation of Axin promotes neurogenesis•Nucleocytoplasmic shuttling of Axin controls IP amplification and differentiation•Axin specifically interacts with GSK-3β or β-catenin to amplify or differentiate IPs

SummaryThe expansion of the mammalian cerebral cortex is safeguarded by a concerted balance between amplification and neuronal differentiation of intermediate progenitors (IPs). Nonetheless, the molecular controls governing these processes remain unclear. We found that the scaffold protein Axin is a critical regulator that determines the IP population size and ultimately the number of neurons during neurogenesis in the developing cerebral cortex. The increase of the IP pool is mediated by the interaction between Axin and GSK-3 in the cytoplasmic compartments of the progenitors. Importantly, as development proceeds, Axin becomes enriched in the nucleus to trigger neuronal differentiation via β-catenin activation. The nuclear localization of Axin and hence the switch of IPs from proliferative to differentiative status are strictly controlled by the Cdk5-dependent phosphorylation of Axin at Thr485. Our results demonstrate an important Axin-dependent regulatory mechanism in neurogenesis, providing potential insights into the evolutionary expansion of the cerebral cortex.Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (113815 K)