The timing of upper-layer neurogenesis is conferred by sequential derepression and negative feedback from deep-layer...

The prevailing view of upper-layer (UL) neurogenesis in the cerebral cortex is that progenitor cells undergo successive rounds of asymmetric cell division that restrict the competence and production of UL neurons later in development. However, the recent discovery of UL fate-committed early progenitors raises an alternative perspective concerning their ontogeny. To investigate the emergence of UL progenitors, we manipulated the timing and extent of cortical neurogenesis in vivo in mice. We demonstrated that UL competence is tightly linked to deep-layer (DL) neurogenesis and that this sequence is determined primarily through derepression of Fezf2 by Foxg1 within a closed transcriptional cascade. We further demonstrated that the sequential acquisition of UL competence requires negative feedback, which is propagated from postmitotic DL neurons. Thus, neocortical progenitors integrate intrinsic and extrinsic cues to generate UL neurons through a system that controls the sequence of DL and UL neurogenesis and to scale the production of intracortical projection neurons based on the availability of their subcortical projection neuron counterparts during cortical development and evolution.