The development of post-mitotic neurons from neural precursors involves three steps: cell cycle exit, cell migration and cell differentiation. The cyclin-dependent kinase inhibitor p27kip1 is known to be involved in controlling cell cycle exit, but now a new study by Guillemot and colleagues shows that it also regulates both migration and differentiation. This multi-talented protein performs each step by a different mechanism.

This multi-talented protein performs each step by a different mechanism.

In the cerebral cortex of p27kip1-null mutant mice embryos, there is a marked decrease in neuronal production (due to fewer cells exiting the cell cycle). However, some neurons are produced, and Guillemot's team were interested in discovering what happens to them so that they could find out whether p27kip1 might be involved in additional developmental tasks. They labelled and followed the fate of the newly born neurons and observed that proportionately fewer cells migrated to the cortical plate from their birth place in the ventricular zone and that fewer cells expressed HuC/D protein, a marker of post-mitotic neurons. These results indicate that both migration and differentiation were impaired in the absence of p27kip1. By overexpressing p27kip1 in the mutant mice, both defects were rescued.

In p27ck embryos, as in p27kip1null embryos, a decrease in neuronal production is observed (p27ck mice express a version of the p27kip1 protein that fails to promote cell cycle exit). However, unlike p27kip1-null embryos, the neurons that are produced in p27ck embryos migrate and differentiate normally. Furthermore, the overexpression of p27ck in p27kip1-knockdown embryos rescues both the migration and differentiation defects, suggesting that the regulation of these processes by p27kip1 involves an independent mechanism from that involved in cell cycle regulation.

Guillemot and colleagues suspected that this new mechanism might involve neurogenin 2 (Ngn2), as it too has been shown to regulate neuronal differentiation and migration. However, when Ngn2 was overexpressed in p27kip1-knockdown mice the differentiation defect was rescued but the migration defect was not. Instead, the migration defect was found to be rescued by overexpression of a dominant-negative form of RhoA — inactivation of RhoA had previously been shown to be necessary for p27kip1-induced fibroblast migration.

To complete the study, the authors went on to determine the different parts of the p27kip1 protein responsible for its two newly discovered functions. Altogether, the work by Guillemot's group provides extensive insight into both the workings of this multi-talented protein and the mechanisms underlying neurogenesis.