The prefrontal cortex (PFC) and its connections with the mediodorsal thalamus are crucial for cognitive flexibility and working memory¹ and are thought to be altered in disorders such as autism^2,3 and schizophrenia^4,5. Although developmental mechanisms that govern the regional patterning of the cerebral cortex have been characterized in rodents^6,7,8,9, the mechanisms that underlie the development of PFC–mediodorsal thalamus connectivity and the lateral expansion of the PFC with a distinct granular layer 4 in primates^10,11 remain unknown. Here we report an anterior (frontal) to posterior (temporal), PFC-enriched gradient of retinoic acid, a signalling molecule that regulates neural development and function^12,13,14,15, and we identify genes that are regulated by retinoic acid in the neocortex of humans and macaques at the early and middle stages of fetal development. We observed several potential sources of retinoic acid, including the expression and cortical expansion of retinoic-acid-synthesizing enzymes specifically in primates as compared to mice. Furthermore, retinoic acid signalling is largely confined to the prospective PFC by CYP26B1, a retinoic-acid-catabolizing enzyme, which is upregulated in the prospective motor cortex. Genetic deletions in mice revealed that retinoic acid signalling through the retinoic acid receptors RXRG and RARB, as well as CYP26B1-dependent catabolism, are involved in proper molecular patterning of prefrontal and motor areas, development of PFC–mediodorsal thalamus connectivity, intra-PFC dendritic spinogenesis and expression of the layer 4 marker RORB. Together, these findings show that retinoic acid signalling has a critical role in the development of the PFC and, potentially, in its evolutionary expansion.

前额皮质 (PFC) 及其与内侧丘脑的连接对于认知灵活性和工作记忆至关重要^{1 ，}并且被认为在自闭症^2,3和精神分裂症^4,5等疾病中会发生改变。尽管控制大脑皮层区域模式的发育机制已在啮齿类动物中得到表征^6,7,8,9 ，但 PFC-内侧丘脑连接性发育和具有独特颗粒层的 PFC 横向扩展的机制 4在灵长类动物中^10,11仍然未知。在这里，我们报告了前部（额叶）到后部（颞叶）富含 PFC 的视黄酸梯度，视黄酸是一种调节神经发育和功能的信号分子^12,13,14,15 ，并且我们在人类和猕猴在胎儿发育早期和中期的新皮质。我们观察到视黄酸的几种潜在来源，包括与小鼠相比，特别是在灵长类动物中视黄酸合成酶的表达和皮质扩张。此外，视黄酸信号传导在很大程度上被CYP26B1（一种视黄酸分解酶）限制在预期PFC中，CYP26B1在预期运动皮层中上调。小鼠的基因缺失表明，通过视黄酸受体 RXRG 和 RARB 的视黄酸信号传导以及 CYP26B1 依赖性分解代谢，参与前额叶和运动区的正确分子模式、PFC-内侧丘脑连接的发育、PFC 内树突第 4 层标记RORB的棘发生和表达。 总之，这些发现表明视黄酸信号传导在 PFC 的发育及其进化扩展中发挥着关键作用。