Progenitor Heterogeneity in the Developing Cortex: Divergent and Complementary Roles of NG2-Progenitors and RGCs

Brain development is a highly coordinated process that arises from a pool of neural progenitor cells (NPCs). Traditionally, research has largely focused on Radial Glial Cells (RGCs), which produce neurons and glia. However, recent findings revealed that the progenitor landscape is more complex and heterogeneous than previously understood. Emerging evidence indicates that NG2 glia, also known as oligodendrocyte precursor cells (OPCs), may contribute to generating other cell types, including neurons and astrocytes. This suggests that NG2 glia, or a specific subset, may act as multipotent NPCs, expanding their role in brain development beyond their known lineage.

We explore the cellular, molecular, and functional differences between NG2- and GFAP- expressing progenitors (NG2-NPCs and GFAP-NPCs) across different developmental stages. Using in-utero electroporation and StarTrack technology, we examined whether these progenitors represent distinct populations and analyzed how their differences influence their functional roles based on cell fate decisions. Our findings uncover functional divergence between NG2-NPCs and GFAP-NPCs, particularly regarding their cell fate decisions. While both populations contribute to the formation of neurons and glial cells, the progeny of NG2-NPCs and GFAP-NPCs differ markedly in their contributions to neurogenesis and gliogenesis. Further, we conducted a comprehensive transcriptomic analysis of NG2-NPCs and GFAP-NPCs to elucidate the molecular basis for these functional differences. This study demonstrates distinct gene expression profiles. While NG2-NPCs show enrichment for genes associated with neurogenesis and synaptic transport, GFAP-NPCs displayed upregulation of genes involved in progenitor cell maintenance. This indicates that each progenitor type is governed by distinct molecular programs, shaping their contributions to brain architecture and function. In summary, our findings underscore the divergent roles of NG2-NPCs and GFAP-NPCs in driving cellular diversity and functional maturation in brain development, providing new insights into how these progenitor populations contribute to neural diversity and brain function.