Neuronal fate resulting from indirect neurogenesis in the mouse neocortex.

Abstract

Excitatory cortical neurons originate from cortical radial glial cells (RGCs). Initially, these neurons were thought to derive directly from RGCs (direct neurogenesis) and be distributed in an inside-out fashion. However, the discovery of indirect neurogenesis, whereby intermediate neuronal progenitors (INPs) generate neurons, challenged this view. To investigate the integration of neurons via these two modes, we developed a method to identify INP progeny and analyze their fate using transgenic mice expressing tamoxifen-inducible Cre recombinase under the neurogenin-2 promoter, alongside thymidine analog incorporation. Their fate was further analyzed using mosaic analysis with double markers in mice. Indirect neurogenesis was prominent during early neurogenesis, generating neuron types that would emerge slightly later than those produced via direct neurogenesis. Despite the timing difference, both neurogenic modes produced fundamentally similar neuron types, as evidenced by marker expression and cortical-depth location. Furthermore, INPs generated pairs of similar phenotype neurons. These findings suggest that indirect neurogenesis, like direct neurogenesis, generates neuron types in a temporally ordered sequence and increases the number of similar neuron types, particularly in deep layers. Thus, both neurogenic modes cooperatively generate a diverse array of neuron types in a similar order, and their progeny populate together to form a coherent cortical structure.