During development of the central nervous system, a lengthening of the cell cycle marks the change from maintenance of progenitor cells to differentiation and neurogenesis. However, the molecular mechanism underlying this process was unclear. Ali et al. (Development 138, 4267–4277; 2011) now demonstrate that this response may be coordinated by multi-site phosphorylation of the transcription factor neurogenin 2 (Ngn2).

Ali et al. found that Ngn2 phosphorylation is dependent on the cell cycle. Nine sites were identified in Ngn2 that could potentially be phosphorylated, and mutation of all nine resulted in a loss of significant phosphorylation, which was found to be dependent on cyclin-dependent kinases (cdks). Expression of this mutant in Xenopus embryos also led to a significant increase in neurogenesis. The authors found that preventing phosphorylation of Ngn2 increased its stability and enhanced its ability to interact with DNA. Interestingly, rather than some of the specific phosphorylation sites being essential or a threshold level of phosphorylation being required, the authors showed that each phosphorylation has an additive effect on the ability of Ngn2 to bind to its promoters. This could allow fine-tuning of the Ngn2 response to the increasing cell length and the inhibition of cdks that accompanies neurogenesis.