Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development
Xiaoxia Peng, et al.
Xiaoxia Peng, et al.
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Research Article Genetics Neuroscience

Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development

Abstract

The Integrator complex plays essential roles in RNA polymerase II (RNAPII) transcription termination and RNA processing. Here, we identify INTS6, a subunit of the Integrator complex, as a novel gene associated with neurodevelopmental disorders (NDDs). Through analysis of large NDD cohorts and international collaborations, we identified 23 families harboring monoallelic likely gene-disruptive or de novo missense variants in INTS6. Phenotypic characterization revealed shared features, including language and motor delays, autism, intellectual disability, and sleep disturbances. Using a nervous-system conditional KO (cKO) mouse model, we show that Ints6 deficiency disrupts early neurogenesis, cortical lamination, and synaptic development. Ints6 cKO mice had a thickened ventricular zone/subventricular zone, thinning of the cortical plate, reduced neuronal differentiation, and increased apoptosis in cortical layer 6. Behavioral assessments of heterozygous mice revealed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants. Molecular analyses further revealed that INTS6 deficiency alters RNAPII dynamics, disrupts transcriptional regulation, and impairs synaptic gene expression. Treatment with a CDK9 inhibitor (CDK9i) reduced RNAPII phosphorylation, thereby limiting its binding to target genes. Notably, CDK9i reversed neurosphere overproliferation and rescued the abnormal dendritic spine phenotype caused by Ints6 deficiency. This work advances understanding of INTS-related NDD pathogenesis and highlights potential therapeutic targets for intervention.

Authors

Xiaoxia Peng, Xiangbin Jia, Hanying Wang, Jingjing Chen, Xiaolei Zhang, Senwei Tan, Xinyu Duan, Can Qiu, Mengyuan Hu, Haiyan Hou, Ilaria Parenti, Alma Kuechler, Frank J. Kaiser, Alicia Renck, Raymond Caylor, Cindy Skinner, Joseph Peeden, Benjamin Cogne, Bertrand Isidor, Sandra Mercier, Gael Nicolas, Anne-Marie Guerrot, Flavio Faletra, Luciana Musante, Lior Cohen, Gaber Bergant, Goran Čuturilo, Borut Peterlin, Andrea Seeley, Kristine Bachman, Julian A. Martinez-Agosto, Conny van Ravenswaaij-Arts, Dennis Bos, Katherine H. Kim, Tobias Bartolomaeus, Zelia Schmederer, Rami Abou Jamra, Erfan Aref-Eshghi, Wenjing Zhao, Yongyi Zou, Zhengmao Hu, Qian Pan, Faxiang Li, Guodong Chen, Jiada Li, Zhangxue Hu, Kun Xia, Jieqiong Tan, Hui Guo

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Figure 6

Ints6 cHET mice lead to social and cognitive impairments.

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Ints6 cHET mice lead to social and cognitive impairments. (A) Heatmaps ...
(A) Heatmaps depicting the movement of WT (n = 14) or cHET (n = 14) mice in a 3-chamber social interaction test. Preference scores were calculated as (S – E)/(S + E) for social versus empty interactions and (S2 – S1)/(S2 + S1) for stranger versus original mouse interactions. Data are reported as mean ± SEM. P values were determined from a 2-tailed unpaired t test. (B) Morris water maze test of spatial learning and memory in Ints6 cHET mice. Latent time (s) during training trials, time in platform quadrant, and distance traveled are measured (n = 14). Data are reported as mean ± SEM. P values were determined from 2-way ANOVA with Bonferroni’s multiple comparisons test and a 2-tailed unpaired Mann-Whitney test. (C) Elevated cross-maze experiments were performed with WT (n = 13) and cHET (n = 14) mice to evaluate anxiety-related behaviors. The experiments statistically analyzed the movement distance and dwell time in both the open and closed arms of the maze. Data are reported as mean ± SEM. P values were determined from a 2-tailed unpaired Mann-Whitney test. (D) Path-tracking images from an open field test, showing movement patterns of WT (n = 14) and cHET (n = 15) mice. Bar graph representing the distance traveled and the time spent in the central area of the open field over 10 minutes. Data are reported as mean ± SEM. P values were determined from a 2-tailed unpaired t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. snRNP, small nuclear ribonucleoprotein.