The similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations^1,2,3,4. Comparative analyses of the prefrontal cortex (PFC), a cerebral cortex region involved in higher-order cognition and complex social behaviours, have identified true and potential human-specific structural and molecular specializations^4,5,6,7,8, such as an exaggerated PFC-enriched anterior–posterior dendritic spine density gradient⁵. These changes are probably mediated by divergence in spatiotemporal gene regulation^{9,10,11,12,13,14,15,16,17}, which is particularly prominent in the midfetal human cortex^15,18,19,20. Here we analysed human and macaque transcriptomic data^15,20 and identified a transient PFC-enriched and laminar-specific upregulation of cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor-δ GRID/GluD-associated synaptic organizer^{21,22,23,24,25,26,27}, during midfetal development that coincided with the initiation of synaptogenesis. Moreover, we found that species differences in level of expression and laminar distribution of CBLN2 are, at least in part, due to Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer. In situ genetic humanization of the mouse Cbln2 enhancer drives increased and ectopic laminar Cbln2 expression and promotes PFC dendritic spine formation. These findings suggest a genetic and molecular basis for the anterior-posterior cortical gradient and disproportionate increase in the Hominini PFC of dendritic spines and a developmental mechanism that may link dysfunction of the NRXN–GRID–CBLN2 complex to the pathogenesis of neuropsychiatric disorders.

不同物种的神经系统之间的异同源于发育限制和特定适应^1,2,3,4。前额叶皮层 (PFC) 是一个涉及高阶认知和复杂社会行为的大脑皮层区域，其比较分析已经确定了真实和潜在的人类特定结构和分子特化^4,5,6,7,8，例如夸大的富含 PFC 的前后树突棘密度梯度⁵。这些变化可能是由时空基因调控的差异介导的^{9,10,11,12,13,14,15,16,17}，这在人类中期胎儿皮质中尤为突出^15,18,19,20. 在这里，我们分析了人类和猕猴的转录组数据^15,20并确定了小脑蛋白 2 (CBLN2)、神经突蛋白 (NRXN) 和谷氨酸受体-δ GRID/GluD 相关突触组织者的短暂 PFC 富集和层流特异性上调^{21,22 ,23,24,25,26,27}，在与突触发生相吻合的中期发育过程中。此外，我们发现CBLN2的表达水平和层状分布的物种差异至少部分是由于视黄酸反应性CBLN2增强子中含有 SOX5 结合位点的 Hominini 特异性缺失。小鼠Cbln2增强子的原位遗传人源化驱动增加和异位层流Cbln2表达并促进 PFC 树突棘形成。这些发现表明前后皮质梯度和树突棘 Hominini PFC 不成比例增加的遗传和分子基础以及可能将 NRXN-GRID-CBLN2 复合体功能障碍与神经精神疾病发病机制联系起来的发育机制。