ERK signaling integrates multiple mechanisms to drive cortical evolutionary expansion
Year: 2026
Type: preprint
Abstract: A critical first step in human evolutionary divergence from chimpanzees and other primates is the production of greatly increased numbers of cortical pyramidal neurons during development and over evolutionary time. This expansion underpins the enlarged human cerebral cortex and, consequently, higher-order cognition and consciousness. However, the cellular and molecular mechanisms driving this progressive increase in cortical neuron number remain incompletely understood. Here we show that elevated ERK signaling in human cortical radial glia (RGs), relative to mouse RGs, arises from evolutionary changes in the developmental expression of existing shared genes. Using the Emx1-Cre line to overexpress MEK1DD , a constitutively active mutant of rat MAP2K1 , we found that enhanced ERK signaling in mouse cortical RGs upregulates cAMP–PKA signaling, along with promoting self-renewal, expanding the RG pool, and accelerating cell cycle progression. Conversely, overexpression of PKA signaling in mouse cortical RGs via in utero electroporation of constitutively active PRKACA mutants (L206R 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. Significance Statement The human brain’s extraordinary cognitive abilities stem from a dramatic increase in cortical neuron numbers during evolution. This study reveals that enhanced ERK signaling in human cortical radial glia neural stem cells, relative to other primates, is a key driver of this expansion. By manipulating this pathway in mice, we demonstrate that ERK coordinates multiple mechanisms—including self-renewal, cell cycle acceleration, and a dynamic interplay with PKA signaling—to boost neuronal output. These findings identify a core molecular axis underlying mammalian cortical evolution and provide a framework for understanding how the human cortex acquired its unique size and, consequently, its remarkable complexity.
Institutions: Fudan University, Zhongshan Hospital, Frontiers Center for Brain Science of the Ministry of Education, Children's Hospital of Fudan University, Tongji University, Yangpu Hospital of Tongji University, Center for Life Sciences, State Key Laboratory of Membrane Biology, Tsinghua University, Chinese Academy of Sciences, Center for Excellence in Brain Science and Intelligence Technology
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7171540783