Dataset Information

The bipolar disorder GWAS risk gene NEK4 modulates circadian fluctuations of murine emotional behaviors and synaptogenesis

ABSTRACT: Through integrative analyses of GWAS summary statistics, population genetic data and expression quantitative trait loci (eQTL) annotations, we found that elevated NEK4 expression in hippocampus was causatively linked to the risk of BD. To examine the biological impact of this gene, we generated NEK4 conditional knock-in mice in pyramidal neurons of the adult forebrain (NEK4 cKI mice) and NEK4 overexpression mice with adeno-associated virus (AAV) mediated in the dorsal hippocampus (NEK4 OE mice). Since NEK4 encodes a serine/threonine kinase, we explored the phosphoproteomic profiles of these mice at different time of the day and compared them with those of the control mice. We isolated the hippocampal proteins of the NEK4 OE mice and the control mice during day and night respectively (n = 3 for each group), and performed phosphorylated 4D-label-free quantitative proteomics analyses. After stringent quality control, 5376 quantifiable phosphorylated peptides were identified in 2415 phosphorylated proteins

ORGANISM(S): Mus <genus>

SUBMITTER: Ming Li

PROVIDER: PXD052190 | iProX | Sat May 11 00:00:00 BST 2024

REPOSITORIES: iProX

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NEK4 modulates circadian fluctuations of emotional behaviors and synaptogenesis in male mice.

Yang Zhi-Hui ZH Cai Xin X Zhang Chu-Yi CY Zhang Qing Q Li Miao M Ding Zhong-Li ZL Guo Yingqi Y Ma Guolan G Yang Chao-Hao CH Guo Lei L Chang Hong H Wang Chuang C Li Ming M Xiao Xiao X

Nature communications 20241024 1

GWASs have linked the 3p21.1 locus, which is associated with the expression levels of NEK4, to bipolar disorder. Here, we use integrative analyses of GWAS statistics and eQTL annotations to establish that elevated NEK4 expression in the hippocampus is associated with an increased risk of bipolar disorder. To further study this association, we generate transgenic male mice that conditionally overexpress NEK4 in the pyramidal neurons of the adult forebrain, or use AAV to overexpress NEK4 in the do ...[more]

PMID: 39448584

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Project description:Single nucleotide polymorphisms (SNPs) within 1p31.1 region have been identified as significant genetic variations associated with depression, and our prior functional genomics pinpointed a regulatory variant rs3101339 among them. However, its precise roles in depression pathogenesis remains elusive. In this study, we employed series analytical and functional approaches, including regulatory element annotation, brain expression quantitative trait loci (eQTL), reporter gene assay, electrophoretic mobility shift assay (EMSA), and precision gene editing. Our results confirmed that rs3101339 is a causal variant within 1p31.1 with its risk allele C upregulating NEGR1 expression. To further investigate the consequences of NEGR1 upregulation, we overexpressed NEGR1 in specific region of the mouse brain (including medial prefrontal cortex (mPFC) and ventral hippocampus (vHIP)) using stereotaxic injection. Behavioral assessments revealed that elevated NEGR1 levels in the brain, particularly in the vHIP, results in working memory impairing and anxiety- and depression-like behaviors in mice. Neuronal sparse labeling assays and electron microscopy revealed that NEGR1 overexpressing in the vHIP leads to neural spine loss and synaptic ultrastructure abnormality. Immunoprecipitation-mass spectrometry (IP-MS) further identified 67 high-confidence proteins that interact with NEGR1, many of them are involved in neurotransmitter exocytosis and synaptic vesicle endocytosis. Notably, Snap25 emerged as a potential central hub within this protein-protein interaction network. Transcriptomic profiling revealed 94 differentially expressed genes in NEGR1-OE (vHIP) mice compared to control mice (P adj < 0.05). These genes were enriched in myelination-related signaling pathways (such as myelination, ensheathment of neurons, axon ensheathment in central nervous system, etc.). Moreover, several myelination-related genes, such as Itgax, Itgb4, Mag, Mbp, Sox10, Bcas1, Trf, Slc8a3, Myrf, and Plp1, were downregulated in NEGR1-OE (vHIP) mice. Together, our findings implicated that the overexpression of the NEGR1 gene in the mouse brain as a potential driver of anxiety- or depression-like phenotypes potentially through impairing synaptic function and myelination.

Dataset Information

The bipolar disorder GWAS risk gene NEK4 modulates circadian fluctuations of murine emotional behaviors and synaptogenesis

Publications

NEK4 modulates circadian fluctuations of emotional behaviors and synaptogenesis in male mice.

Similar Datasets

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