Several transcription factors are essential determinants of a cortical projection neuron identity, but their mode of action (instructive versus permissive) and downstream genetic cascades remain poorly defined. Here, we demonstrate that the proneural basic helix-loop-helix (bHLH) gene Ngn2 instructs a partial cortical identity when misexpressed in ventral telencephalic progenitors, inducing ectopic marker expression in a defined temporal sequence, including early (24 h; Nscl2), intermediate (48 h; BhlhB5), and late (72 h; NeuroD, NeuroD2, Math2, and Tbr1) target genes. Strikingly, cortical gene expression was much more rapidly induced by Ngn2 in the dorsal telencephalon (within 12 to 24 h). We identify the bHLH gene Math3 as a dorsally restricted Ngn2 transcriptional target and cofactor, which synergizes with Ngn2 to accelerate target gene transcription in the cortex. Using a novel in vivo luciferase assay, we show that Ngn2 generates only ϳ60% of the transcriptional drive in ventral versus dorsal telencephalic domains, an activity that is augmented by Math3, providing a mechanistic basis for regional differences in Ngn2 function. Cortical bHLH genes thus cooperate to control transcriptional strength, thereby temporally coordinating downstream gene expression.Advanced cognitive functioning is controlled by the cerebral cortex, which includes the six-layered neocortex, a brain region mainly comprised of excitatory, glutamatergic projection neurons and a smaller number of inhibitory, GABAergic (where GABA is ␥-aminobutyric acid) interneurons. While all cortical projection neurons share a pyramidal morphology, dorsal telencephalic origin, and glutamatergic neurotransmitter phenotype, they also display laminar and region-specific differences in morphology, projection pattern, and gene expression (47, 57). The homeodomain transcription factors Lhx2, Pax6, and Emx2 are considered cortical selector genes as they are each required for cortical development (48,49). Strikingly, in Pax6; Emx2 double mutants, the neocortex is converted to basal ganglia, a ventral telencephalic territory (49). A similar conversion of dorsal (cortical) to ventral regional identity also occurs in mice carrying mutations in ␤-catenin and Gli3, downstream transcriptional effectors in the Wnt and Shh signaling pathways, respectively (6,72,73). Moreover, ventral, GABAergic rather than dorsal, glutamatergic neurons differentiate in Ngn2

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