Adaptive Clonal Expansion Shapes Brain Development

Embryonic neural stem/progenitor cells (NSPCs) exhibit remarkable proliferative plasticity, allowing them to fully recover neuronal populations even after substantial cell loss 1,2. However, it remains unclear whether all embryonic NSPCs respond to brain lesions. To address this, we developed a mouse model to investigate NSPC proliferation dynamics, hypothesizing that the loss of progenitor cells would induce fitness competition among NSPCs. In this model, half of the founder NSPCs were ablated using diphtheria toxin A at the onset of neurogenesis, yet the surviving cells regenerated a brain containing all neuronal types within five of the total twenty embryonic days. Analysis of allelic variants revealed overrepresented somatic variants, indicating that only a small fraction of NSPCs underwent significant clonal expansion during early neurogenesis. Modelling proliferation dynamics predicted that as few as 10% of NSPCs could produce 83% of neurons by the time of birth. Single nucleotide substitution analysis suggested a potential link to oxidative metabolism in some of the expanded clones. Moreover, single-cell transcriptomics showed delayed development and a reduced NSPC pool as consequences of adaptive clonal expansion. Our findings highlight that NSPC exhibit varying expansion potential and that adaptive clonal expansion indirectly altered neuronal cell composition in the brain.