Hirata Group / Brain Function Laboratory

Neuronal fate resulting from indirect neurogenesis in the mouse neocortex

Hatanaka Y, Yamada K, Eritate T, Kawaguchi Y, Hirata T.

Cerebral Cortex Volume 34, Issue 11, November 2024, bhae439 DOI:10.1093/cercor/bhae439

The mammalian neocortex is characterized by a six-layered structure, with each layer containing neurons that perform distinct functions. These neurons are derived from neural stem cells, known as radial glial cells (RGCs), located in the ventricular zone. During neurogenesis, RGCs divide by two distinct modes: direct neurogenesis, where RGCs generate neurons directly, and indirect neurogenesis, where RGCs first produce intermediate neural progenitors (INPs) that subsequently differentiate into neurons. Although these differentiation modes have been demonstrated through in vitro imaging studies, their contributions to cortical structure formation remain poorly understood.

We developed a method to identify neurons generated via indirect neurogenesis to address this issue. First, we demonstrated that tamoxifen administration to Neurog2^CreER mice induces recombination in cells committed to becoming neurons, including INPs. Second, we distinguished neurons generated via indirect neurogenesis by allowing them to incorporate a thymidine analog. Using this approach, we found that indirect neurogenesis is prominent during the early stages of cortical neurogenesis and that both neurogenesis modes generate similar neuronal types in the same temporal sequence. Moreover, by crossing Neurog2^CreER mice with MADM mice, we demonstrated that INPs undergo a single division to produce two neurons exhibiting similar morphology.

These findings indicate that direct and indirect neurogenesis cooperatively generate a diverse array of neuronal types in a temporally coordinated manner, and their progeny populate together to form a coherent cortical structure. This study also provides important insights into the mechanisms underlying neocortical expansion during evolution.

Figure: (A) Neurons are generated from radial glial cells (RGCs), which exhibit two distinct modes of division during neurogenesis: (1) direct neurogenesis, where an RGC directly produces a neuron, and (2) indirect neurogenesis, where an RGC generates an intermediate neural progenitor (INP) that subsequently produces neurons. (B) Indirect neurogenesis is particularly prevalent during the early stages of neurogenesis. Neurons generated through both direct and indirect neurogenesis differentiate into similar neuronal types in a temporally ordered fashion. Indirect neurogenesis likely functions to amplify the production of similar types of neurons efficiently.
L6 CT, layer 6 corticothalamic projection neuron; SC, subcortical projection neuron; IT, intratelencephalic projection neuron.