Journal article
WNT signalling control by KDM5C during development affects cognition
- Abstract:
- Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability, 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 27.3MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-024-07067-y
Authors
+ National Center for Advancing Translational Sciences
More from this funder
- Funder identifier:
- https://ror.org/04pw6fb54
- Grant:
- UL1 TR002541
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 627
- Issue:
- 8004
- Pages:
- 594-603
- Place of publication:
- England
- Publication date:
- 2024-02-21
- Acceptance date:
- 2024-01-12
- DOI:
- EISSN:
-
1476-4687
- ISSN:
-
0028-0836
- Pmid:
-
38383780
- Language:
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English
- Pubs id:
-
1632060
- Local pid:
-
pubs:1632060
- Deposit date:
-
2024-04-05
Terms of use
- Copyright holder:
- Karwacki-Neisius et al.
- Copyright date:
- 2024
- Rights statement:
- © 2024, The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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