The progenitor basis of cortical projection neuron diversity.

Diverse glutamatergic projection neurons (PNs) mediate myriad processing streams and output channels of the cerebral cortex. Yet, how different types of neural progenitors, such as radial glia (RGs) and intermediate progenitors (IPs), produce PN diversity, and hierarchical organization remains unclear. A fundamental issue is whether RGs constitute a homogeneous, multipotent lineage capable of generating all major PN types through a temporally regulated developmental program, or whether RGs comprise multiple transcriptionally heterogenous pools, each fated to generate a subset of PNs. Beyond RGs, the role of IPs in PN diversification remains underexplored. Addressing these questions requires tracking PN developmental trajectories with cell-type resolution – from transcription factor-defined RGs and IPs to their PN progeny, which are defined not only by laminar location but also by projection patterns and gene expression. Advances in cell-type resolution genetic fate mapping, axon tracing, and spatial transcriptomics may provide the technical capability for answering these fundamental questions. • The hierarchical organization of PN types is jointly defined by their transcriptome, anatomy, and physiology. • Lineage tracing needs to distinguish TF-defined RGs as well as projection and transcriptionally defined PNs. • Emerging evidence of fate-restricted RGs is not mutually exclusive with models of multipotency and temporal competence. • Direct and indirect neurogenesis differentially contribute to PN diversity. [ABSTRACT FROM AUTHOR]