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WNT signalling control by KDM5C during development affects cognition
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WNT signalling control by KDM5C during development affects cognition
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Journal Article
WNT signalling control by KDM5C during development affects cognition
2024
Overview
Although
KDM5C
is one of the most frequently mutated genes in X-linked intellectual disability
1
, 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.
The demethylase KDM5C, mutations in which often lead to intellectual disability, is identified as a crucial player in regulating the precise timing of neurodevelopment together with the WNT signalling pathway.
