Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1,000-fold increase in the number of neurons in the 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 coexpression of NKX2-2 and OLIG2 that give rise to spinal motor neurons. Unlike classical OLIG2⁺ motor neuron progenitors that give rise to two motor neurons each, OLIG2⁺/NKX2-2⁺ ventral motor neuron progenitors remain cycling longer, yielding ~5 times more motor neurons that are biased toward later-born, FOXP1-expressing subtypes. Knockout of NKX2-2 converts ventral motor neuron progenitors into classical motor neuron progenitors. Such new progenitors may contribute to the increased production of human motor neurons required for the generation of larger, more complex nervous systems.

与小鼠相比，发育中的人类神经发生的持续时间长 ~10 倍，导致 CNS 中神经元的数量增加了 >1,000 倍。为了确定导致这种差异的分子和细胞机制，我们使用干细胞分化系统研究了人类和小鼠运动神经发生，该系统概括了物种特异性的发育规模。人和小鼠单细胞基因表达数据的比较确定了以产生脊髓运动神经元的 NKX2-2 和 OLIG2 共表达为特征的人类特异性祖细胞。与每个祖先产生两个运动神经元的经典 OLIG2 ⁺ 运动神经元祖细胞不同，OLIG2 ⁺ / NKX2-2 ⁺ 腹侧运动神经元祖细胞的循环时间更长，产生的运动神经元偏向于晚生的表达 FOXP1 的亚型。敲除 NKX2-2 将腹侧运动神经元祖细胞转化为经典运动神经元祖细胞。这种新的祖细胞可能有助于增加产生更大、更复杂的神经系统所需的人类运动神经元的产生。