Extended Data Fig. 10. A single Wnt3a injection induces and Wnt signaling inhibition rescues KDM5C-associated ID phenotypes, respectively.
a, Representative heatmaps in the Elevated Plus Maze for PBS and Wnt3a injected mice. b, Number of entries into the center in the Open field test (left), time spent in the periphery (middle) and the center (right) in the Open field test. Data are represented as mean ± SEM. 13 PBS and 14 Wnt3a injected mice were investigated. The p-values by one-tailed unequal variance t-test are indicated. P < 0.05 was considered statistically significant. c, Animation of sampling sites for spine density analysis provided by Neurodigitech. d, Expression of the germ line genes DDX3Y, DNAH1 and the DNA methyltransferase DNMT3b at day 32 in the indicated cell lines extracted from RNA-seq data. Data are represented as mean ± SD of 3 independent experiments. The p-values by two-tailed unpaired Student’s t-test are indicated. P < 0.05 was considered statistically significant. e, Model: KDM5C does not efficiently bind to Wnt signaling genes in Mutant cells, which have significantly reduced KDM5C levels. Subsequently, early premature neurons (EN) are briefly increased but more importantly the transition from primary progenitor cells (PP) to intermediate progenitors (iPC) is delayed, which results in a significant delay of neuron (N) expression and proper inter-neuronal connectivity with reduced spine density. During this particular time period of neuronal development, Wnt sensitivity is elevated such that only transient Wnt perturbation is sufficient to have either therapeutic effects when Wnt is inhibited in Mutant cells or can induce disease phenotypes when Wnt3a is added to Corrected cells resulting in persistent cognitive impairments in adult mice. Model was in part created with BioRender.com.