WNT signalling control by KDM5C during development affects cognition

Violetta Karwacki-Neisius (), Ahram Jang, Engin Cukuroglu, Albert Tai, Alan Jiao, Danilo Predes, Joon Yoon, Emily Brookes, Jiekai Chen, Aimee Iberg, Florian Halbritter, Katrin Õunap, Jozef Gecz, Thorsten M. Schlaeger, Shannan Ho Sui, Jonathan Göke, Xi He, Maria K. Lehtinen, Scott L. Pomeroy and Yang Shi ()
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Violetta Karwacki-Neisius: Harvard Medical School
Ahram Jang: Harvard Medical School
Engin Cukuroglu: Genome Institute of Singapore
Albert Tai: Tufts University School of Medicine
Alan Jiao: Harvard Medical School
Danilo Predes: Harvard Medical School
Joon Yoon: The Harvard Chan School of Public Health, Bioinformatics Core
Emily Brookes: Harvard Medical School
Jiekai Chen: Harvard Medical School
Aimee Iberg: Harvard Medical School
Florian Halbritter: Children’s Cancer Research Institute, St Anna Kinderkrebsforschung
Katrin Õunap: Tartu University Hospital
Jozef Gecz: University of Adelaide
Thorsten M. Schlaeger: Boston Children’s Hospital
Shannan Ho Sui: The Harvard Chan School of Public Health, Bioinformatics Core
Jonathan Göke: Genome Institute of Singapore
Xi He: Harvard Medical School
Maria K. Lehtinen: Boston Children’s Hospital
Scott L. Pomeroy: Broad Institute of MIT and Harvard
Yang Shi: Harvard Medical School

Nature, 2024, vol. 627, issue 8004, 594-603

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07067-y

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