Regional Differences in Progenitor Consumption Dynamics Shape Brain Growth during Development

Abstract

Developing mammalian brains are characterized by disproportionate growth of the forebrain compared to other regions. How this localized expansion occurs is, however, largely unknown. To address this, we identified region-specific neurogenic patterns by creating a single-cell-resolution birthdate atlas of the mouse brain (https://www.neurobirth.org). We report that in forebrain regions, neurogenesis is sustained compared to the hindbrain, where neurogenesis is transient and limited to early brain development. Sustained forebrain neurogenesis reflects lengthened cell cycle and reduced consumptive divisions of ventricular zone progenitors, resulting in a preserved germinal cell pool. Using single-cell RNA sequencing, we identify functional molecular programs of ventricular zone progenitors that spatially and temporally regulate progenitor cycling properties, including through loss-of-function of the forebrain-enriched mitochondrial membrane protein Fam210b. These results reveal a parsimonious mechanism to locally regulate neuronal production, in which the time window during which progenitors generate cells is a critical determinant of region-specific brain expansion.