Identification of novel genes with enriched expression in human intermediate progenitors reveals a key role for CDKN3 in cortical development.

Abstract

The evolutionary expansion of the human neocortex relies on species-specific features of intermediate progenitor cells (IPCs), including enhanced proliferation and neuronal production. The transcriptomic differences in IPCs underlying their differential capacity across species remain elusive. To identify the transcriptional signature of human IPCs (hIPCs), we isolated TBR2-positive IPCs from developing human neocortex. A comparative genome-wide expression analysis of IPC transcriptional profiles from human and mouse outlined genes preferentially expressed in hIPCs encoding key factors of cell signaling, transcriptional regulation, and proliferation. Mutations in several hIPC-specific genes were linked to cortical malformations and brain tumors. Functional experiments involving hIPC-specific overexpression of CDKN3 in developing mouse cortex validated the pivotal role of CDKN3 in IPC proliferation and neurogenesis, and supported its identification as a key determinant of hIPC biogenesis. Our findings offer new insights into the molecular features of hIPCs underlying their capacity to mediate the evolutionary expansion of the human neocortex.