Identification of a set of transcriptional regulators involved in the temporal regulation of neuronal subtype differentiation

Complex neural activity in the mammalian central nervous system are achieved through the coordinated function of diverse neuronal subtypes. The sequential generation of distinct types of neurons from neural progenitor cells during development is a key process in establishing this complexity. However, how this temporal specification of neuronal identities is regulated across different brain regions during development remains only partially understood. Here, we identify PHF21B, ZFP7, and ZFP57 as critical regulators that control the transition from the generation of early-born to late-born neurons by neural progenitor cells in the developing mouse cortex and ganglionic eminence. Combinatorial overexpression of these factors in developmentally advanced progenitors that normally generate late-born neurons led to a prolonged generation of early-born neuronal subtypes. Conversely, simultaneous knockdown of these genes markedly reduced generation of early-born neurons. Because these factors are predicted to function as transcriptional regulators involved in heterochromatin formation at their target genomic loci, our findings suggest the presence of a shared epigenetic mechanism that governs the temporal specification of neurons across multiple regions of the developing brain.