Regional Differences in Progenitor Consumption Dynamics Shape Brain Growth during Development

The structure of vertebrate brains emerges from a shared template where three primary regions — the hindbrain, midbrain, and forebrain — develop during embryogenesis to establish the circuits responsible for distinct functions. While the molecular mechanisms underlying the segmentation of the neural tube into these regions are relatively well understood, how their relative expansion is regulated during embryogenesis remains largely unknown. To address this question, we first generated a single-cell resolution atlas of birthdate across the entire mouse brain (https://www.neurobirth.org), which we next leveraged to identify brain-region-specific neurogenic patterns and investigate underlying molecular mechanisms. We show that in brain regions that expand, such as the neocortex, neurogenesis is sustained (sustained neurogenic regions), while it is limited to the first few days of brain development in hindbrain regions that are comparatively less developed (transient neurogenic regions). We demonstrate that sustained cortical neurogenesis is made possible by a progressive lengthening of the cell cycle and associated lower levels of consumptive divisions in apical progenitors (AP), which preserve the progenitor pool for longer periods. Finally, using single-cell RNA sequencing of AP across the developing brain, we identify spatio-temporal molecular determinants of AP cycling behavior and demonstrate a critical role for the mitochondrial membrane protein Fam210b in regulating region-specific cycling properties. These results identify a parsimonious mechanism to regulate neuronal production in different parts of the brain, in which the time window during which neurons are generated appears to be a critical determinant of a region’s expansion during development and evolution.