Temporal Differences in Progenitor Metabolism Shape Regional Brain Growth during Development

Mammalian brain development is characterized by disproportionate forebrain expansion, yet the mechanisms underlying this regional growth specificity remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors, maintaining its germinal pool. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late forebrain-enriched mitochondrial protein Fam210b as a key regulator using in vivo gain- and loss-of-function experiments. Fam210b elongates mitochondria and increases lactate production, which promotes progenitor self-renewing divisions and, ultimately, larger clonal size of their progeny. Together, these findings indicate spatiotemporal heterogeneity in mitochondrial function regulates progenitor cycling behavior and regional neuronal production during brain development. CD1 mice embryo were electroporated at E14 in the neocortex and collected for 3' single nucleus transcriptomics at E15