Species-specific progenitor sub-domain extends neurogenesis and increases human motor neuron production

Abstract Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1000-fold increase in the number of neurons in the central nervous system (CNS). To identify molecular and cellular mechanisms contributing to this difference, we studied human and mouse motor neurogenesis using a stem cell differentiation system that recapitulates species-specific scales of development. Comparison of human and mouse single-cell gene expression data identified human-specific progenitors characterized by co-expression of NKX2-2 and OLIG2, two transcription factors that are mutually exclusive during mouse motor neurogenesis. The same progenitor population has been reported in the human embryonic spinal cord1, 2, but its function remained controversial. Lineage tracing revealed that these cells give rise to spinal motor neurons. But unlike classical OLIG2+ motor neuron progenitors (pMNs) that give rise to two motor neurons each, OLIG2+/NKX2-2+ ventral motor neuron progenitors (vpMNs) remain cycling longer, leading to prolonged and expanded neurogenesis yielding ~5 times more motor neurons that preferentially contribute to the later-born FOXP1-expressing subtypes. NKX2-2 is a master regulator of this behavior as knockout of this transcription factor converts vpMNs into cells functioning as classical pMNs. In summary, increased production of human motor neurons relies on the emergence of a novel progenitor sub-domain, underscoring the diversity of developmental mechanisms employed to generate larger, more complex nervous systems.