4/3/2024 0 Comments Annotating an article keyOur findings not only provide significant new insights into the fundamental mechanisms that regulate neuronal development but also decipher how events happening early in the embryo can form the basis for impairments in memory and anxiety later in life. Therefore, insights into the function of KDM5C in brain development, especially in humans, are needed and crucial for understanding the pathology of neuronal diseases. However, how KDM5C directs neuronal differentiation and which developmental time points are affected by KDM5C loss and lead to ID phenotypes are unknown. The Kdm5c knockout (KO) mouse model recapitulates many clinical features observed in human patients with KDM5C mutations, including learning and memory deficits 13, 14. Patients with KDM5C mutations suffer from mild to severe ID that is often accompanied by microcephaly, behavioural disturbance and epilepsy 12. Thus, KDM5C provides an important paradigm for studying the neurodevelopmental causes of cognitive dysfunction. Mutations in KDM5C are involved in X-linked ID and in autism spectrum disorder 1, 11. The histone H3 lysine 4 dimethyl and trimethyl specific demethylase KDM5C 9, 10 is one such crucial epigenetic regulator. However, the regulatory mechanisms that mediate the timing of the numerous molecular and cellular events vital for neuronal development and their contributions to disease development remain incompletely understood 5.Ī plethora of neurodevelopmental disorders, including intellectual disability (ID), autism spectrum disorder, attention-deficit hyperactivity disorder and cerebral palsy, which affect one in six children in the United States alone 6, have been genetically linked to chromatin-modifying enzymes and other epigenetic regulators 7, 8. Substantial efforts have been made to understand the role of transcriptional regulators in controlling the differentiation of neuronal cell types during early neuronal development 2, 3, 4. Neurodevelopment is a highly orchestrated process whereby progenitors and neurons emerge during development in a rigorously coordinated temporal and spatial order. 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. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. 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. 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. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. Yang Shi ORCID: /0000-0001-9713-1709 1, 6Īlthough 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.WNT signalling control by KDM5C during development affects cognition
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