Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability¹, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Specifically, there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis. Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells and to induce these changes in wild-type cells. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. The results also increase our general understanding of memory and anxiety formation, with the identification of WNT functioning in a transient nature to affect long-lasting cognitive function.

尽管KDM5C是 X 连锁智力障碍中最常见的突变基因之一¹ ，但导致认知障碍的确切机制仍不清楚。在这里，我们使用人类患者衍生的诱导多能干细胞和Kdm5c敲除小鼠进行细胞、转录组、染色质和行为研究。 KDM5C 被认为是确保神经发育在适当的时间范围内发生的保障措施，神经发育的破坏会导致智力障碍。具体来说，存在一个发育窗口，在此期间 KDM5C 直接控制 WNT 输出，以调节初级祖细胞向中间祖细胞的及时转变，从而调节神经发生。在特定时间使用 WNT 信号调节剂进行治疗表明，仅规范 WNT 信号通路的短暂改变就足以挽救患者来源细胞中的转录组和染色质景观，并在野生型细胞中诱导这些变化。值得注意的是，在这个发育时期抑制 WNT 也可以挽救Kdm5c敲除小鼠的行为变化。相反，向野生型胚胎小鼠的大脑中单次注射 WNT3A 会引起焦虑和记忆改变。我们的工作将 KDM5C 确定为神经发育的关键哨兵，并为KDM5C突变相关的智力障碍提供了新的线索。研究结果还增加了我们对记忆和焦虑形成的一般理解，并确定了 WNT 的短暂功能会影响长期的认知功能。