Post-translational Control of the Temporal Dynamics of Transcription Factor Activity Regulates Neurogenesis

Neurogenesis is initiated by the transient expression of the highly conserved proneural proteins, bHLH transcriptional regulators. Here, we discover a conserved post-translational switch governing the duration of proneural protein activity that is required for proper neuronal development. Phosphorylation of a single Serine at the same position in Scute and Atonal proneural proteins governs the transition from active to inactive forms by regulating DNA binding. The equivalent Neurogenin2 Threonine also regulates DNA binding and proneural activity in the developing mammalian neocortex. Using genome editing in Drosophila, we show that Atonal outlives its mRNA but is inactivated by phosphorylation. Inhibiting the phosphorylation of the conserved proneural Serine causes quantitative changes in expression dynamics and target gene expression resulting in neuronal number and fate defects. Strikingly, even a subtle change from Serine to Threonine appears to shift the duration of Atonal activity in vivo, resulting in neuronal fate defects. [Display omitted] •Proneural transcription factors driving neurogenesis show fast temporal dynamics•A conserved phosphorylation site controls the temporal dynamics of these factors•Inhibiting proneural phosphorylation alters the number of fate of nascent neurons•Subtle quantitative interference with phosphorylation affects neuronal cell fate The active lifetime of a family of transcription factors is regulated by phosphorylation, and even subtle changes to the timing of inactivation can disrupt the numbers and identities of neurons specified during development.