ERK signaling integrates multiple mechanisms to drive cortical evolutionary expansion

Conversely, overexpression of PKA signaling in mouse cortical RGs via in utero electroporation of constitutively active PRKACA mutants (L205R or W196G) reduces ERK activity, prolongs the cell cycle, suppresses SHH–SMO and YAP/TAZ pathway activity, and blocks ependymal gliogenesis. Together, our results demonstrate that ERK and PKA signaling in cortical RGs engage a dynamic balance of synergistic and antagonistic interactions.

This interplay couples evolutionarily enhanced ERK and PKA activities to increased cortical RG numbers, prolonged cell cycle progression, and an extended neurogenic period, which collectively culminate in a marked increase in neuronal production. We conclude that heightened ERK pathway activity in cortical RGs serves as a central driver of progressive neocortical expansion across mammalian evolution.