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Zbtb16 regulates social cognitive behaviors and neocortical development

ABSTRACT: Recent genomic studies suggest that a single gene is involved in multiple diseases, however it is unclear what mechanism destined for different diseases by a single gene. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how ZBTB16 fates ASD or SCZ are unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of the single gene ZBTB16 in ASD and SCZ.

ORGANISM(S): Mus musculus

PROVIDER: GSE155424 | GEO | 2021/05/12

REPOSITORIES: GEO

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Zbtb16 regulates social cognitive behaviors and neocortical development

Project description:Zbtb16 regulates social cognitive behaviors and neocortical development

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Project description:The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.

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Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

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Project description:Lung adenocarcinoma is a malignant tumor with high morbidity and mortality. ZBTB16 plays a double role in various tumors; however, the potential mechanism of ZBTB16 in the pathophysiology of lung adenocarcinoma has yet to be elucidated. We herein observed a decreased expression of ZBTB16 mRNA and protein in lung adenocarcinoma and a significantly increased DNA methylation level of ZBTB16 in patients with lung adenocarcinoma. Analysis of public databases and patients’ clinical data indicated a close association between ZBTB16 and patient survival. Ectopic expression of ZBTB16 in lung adenocarcinoma cells significantly inhibited cell proliferation, invasion, and migration. It also induced cell cycle arrest in the S phase. Meanwhile, mitotic catastrophe was induced, and DNA damage and apoptosis occurred. In line with these findings, the overexpression of ZBTB16 in xenograft mice resulted in the inhibition of tumor growth. Comprehensive analysis showed that WDHD1 was a potential target for ZBTB16. The overexpression of both isoforms of WDHD1 significantly reversed the ZBTB16-mediated inhibition of lung adenocarcinoma proliferation and cell cycle. These studies suggest that ZBTB16 impedes the progression of lung adenocarcinoma by interfering with WDHD1 transcription, making it a potential novel therapeutic target in the management of lung adenocarcinoma.

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Project description:Autism Spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder where patients have impaired social behavior and communication, and restricted interests. Although various studies have been carried out to unveil the mechanisms associated with ASD, its pathophysiology is still poorly understood. Genetic variants on CNTNAP2 have been found and considered representative ASD genetic risk factors, and disruption of Cntnap2 causes ASD phenotypes in mice. Here, we performed an integrative multi-omics analysis by combining quantitative proteometabolomics data of Cntnap2 knockout (KO) mice with multi-omics data from ASD patients and forebrain organoids to elucidate Cntnap2-dependent molecular networks of ASD. First, we found Cntnap2-associated molecular signatures and cellular processes by conducting mass spectrometry-based proteometabolomic analysis of the medial prefrontal cortex of the Cntnap2 KO mouse model. Then, we narrowed these identified processes into bona fide ASD molecular processes by incorporating multi-omics data of ASD patients' prefrontal cortex. Further, we mapped cell-type-specific ASD networks by reanalyzing single-cell RNA-seq data of forebrain organoids derived from patients with CNTNAP2 mutation. Finally, we constructed a Cntnap2-associated ASD network model consisting of mitochondrial dysfunction, axonal impairment, and synaptic activity. Our results may shed light on understanding of the Cntnap2-dependent molecular networks of ASD.

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