Asymmetric neuronal expansion is thought to drive evolutionary transitions between lissencephalic and gyrencephalic cerebral cortices. We report that Neurog2 and Ascl1 proneural genes together sustain neurogenic continuity and lissencephaly in rodent cortices. Using transgenic reporter mice and human cerebral organoids, we found that Neurog2 and Ascl1 expression defines a continuum of four lineage-biased neural progenitor cell (NPC) pools. Double⁺ NPCs, at the hierarchical apex, are least lineage restricted due to Neurog2-Ascl1 cross-repression and display unique features of multipotency (more open chromatin, complex gene regulatory network, G₂ pausing). Strikingly, selectively eliminating double⁺ NPCs by crossing Neurog2-Ascl1 split-Cre mice with diphtheria toxin-dependent “deleter” strains locally disrupts Notch signaling, perturbs neurogenic symmetry, and triggers cortical folding. In support of our discovery that double⁺ NPCs are Notch-ligand-expressing “niche” cells that control neurogenic periodicity and cortical folding, NEUROG2, ASCL1, and HES1 transcript distribution is modular (adjacent high/low zones) in gyrencephalic macaque cortices, prefiguring future folds.

不对称的神经元扩张被认为驱动了 lissencephalic 和 gyrencephalic 大脑皮层之间的进化转变。我们报告Neurog2和Ascl1 原神经基因共同维持啮齿动物皮质中的神经源性连续性和无脑畸形。使用转基因报告小鼠和人类大脑类器官，我们发现Neurog2和Ascl1表达定义了四个谱系偏向神经祖细胞 (NPC) 池的连续体。由于 Neurog2-Ascl1 交叉抑制，Double ⁺ NPC 在层次结构顶点受到的谱系限制最少，并显示出多能性的独特特征（更开放的染色质、复杂的基因调控网络、G ₂暂停）。引人注目的是，通过将Neurog2-Ascl1 split-Cre 小鼠与依赖白喉毒素的“删除”品系杂交，选择性地消除双⁺ NPC，局部破坏了 Notch 信号传导，扰乱了神经源性对称性，并触发了皮质折叠。为了支持我们的发现，即双⁺ NPC 是表达 Notch 配体的“利基”细胞，控制神经源性周期性和皮质折叠，NEUROG2、ASCL1和HES1转录本分布在回脑猕猴皮质中是模块化的（相邻的高/低区），预示着未来折叠。