小柯机器人

美国哈佛大学施扬等研究人员合作发现，发育过程中KDM5C对WNT信号的控制影响认知能力。这一研究成果于2024年2月21日在线发表在国际学术期刊《自然》上。

研究人员利用源自患者的诱导多能干细胞和Kdm5c基因敲除小鼠进行细胞、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进行的保障，其破坏会导致智力残疾。具体来说，在发育窗口期，KDM5C可直接控制WNT的输出，从而调节初级祖细胞向中间祖细胞的及时过渡，进而调节神经发生。在特定时间用WNT信号调节剂处理后发现，只需短暂改变典型的WNT信号通路，就足以挽救患者衍生细胞的转录组和染色质景观，并诱导野生型细胞发生这些变化。

值得注意的是，在这一发育阶段抑制WNT也能挽救Kdm5c基因敲除小鼠的行为变化。相反，在野生型胚胎小鼠大脑中注射一次WNT3A会导致焦虑和记忆改变。这项研究确定了KDM5C是神经发育的关键哨点，并为KDM5C基因突变相关的智力残疾提供了新的线索。研究结果还增加了人们对记忆和焦虑形成的总体了解，并确定了WNT在影响长期认知功能方面的短暂作用。

研究人员表示，尽管KDM5C是X连锁智力障碍中最常见的突变基因之一，但导致认知障碍的确切机制仍然未知。

附：英文原文

Title: WNT signalling control by KDM5C during development affects cognition

Author: Karwacki-Neisius, Violetta, Jang, Ahram, Cukuroglu, Engin, Tai, Albert, Jiao, Alan, Predes, Danilo, Yoon, Joon, Brookes, Emily, Chen, Jiekai, Iberg, Aimee, Halbritter, Florian, unap, Katrin, Gecz, Jozef, Schlaeger, Thorsten M., Ho Sui, Shannan, Gke, Jonathan, He, Xi, Lehtinen, Maria K., Pomeroy, Scott L., Shi, Yang

Issue&Volume: 2024-02-21

Abstract: 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.

DOI: 10.1038/s41586-024-07067-y

Source: https://www.nature.com/articles/s41586-024-07067-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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