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Progenitor cells undergo a series of stable identity transitions on their way to becoming fully differentiated cells with unique identities. Each cellular transition requires that new sets of genes are expressed, while alternative genetic programs are concurrently repressed. Here, we investigated how the proneural gene  Neurog2  simultaneously activates and represses alternative gene expression programs in the developing neocortex. By comparing the activities of transcriptional activator ( Neurog2-VP16 ) and repressor ( Neurog2-EnR ) fusions to wild-type  Neurog2 , we first demonstrate that  Neurog2  functions as an activator to both extinguish Pax6 expression in radial glial cells and initiate Tbr2 expression in intermediate neuronal progenitors. Similarly, we show that  Neurog2  functions as an activator to promote the differentiation of neurons with a dorsal telencephalic (i.e., neocortical) identity and to block a ventral fate, identifying 2  Neurog2 -regulated transcriptional programs involved in the latter. First, we show that the Neurog2-transcriptional target  Tbr2  is a direct transcriptional repressor of the ventral gene  Ebf1 . Secondly, we demonstrate that  Neurog2  indirectly turns off  Etv1  expression, which in turn indirectly regulates the expression of the ventral proneural gene  Ascl1. Neurog2  thus activates several genetic off-switches, each with distinct transcriptional targets, revealing an unappreciated level of specificity for how  Neurog2  prevents inappropriate gene expression during neocortical development.

Neurog2 Simultaneously Activates and Represses Alternative Gene Expression Programs in the Developing Neocortex