Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability

Coba, Marcelo P.; Ramaker, Marcia J.; Ho, Emily V.; Thompson, Summer L.; Komiyama, Noboru H.; Grant, Seth G. N.; Knowles, James A.; Dulawa, Stephanie C.

doi:10.1038/s41598-018-20610-y

Cited by 37 publications

(35 citation statements)

References 82 publications

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“…Several of these interactions have been previously observed to modulate neuronal function in model systems. For example, SHANK3 interacts with DLG1 through the mediator protein DLGAP1 to influence post-synaptic density in mice [66] and binds to proteins in the Rac1 complex, including PAK2, to regulate synaptic structure [67,68]. These results suggest that homologs of 3q29 genes interact with key developmental genes in conserved pathways to modify cellular phenotypes.…”

Section: Homologs Of 3q29 Genes Interact With Canonical Neurodevelopmmentioning

confidence: 98%

NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

et al. 2020

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The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development.

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Section: Homologs Of 3q29 Genes Interact With Canonical Neurodevelopmmentioning

confidence: 98%

NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

et al. 2020

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“…DLG associated protein 1 (DLGAP1), also known as Disks large-associated protein 1 (DAP-1), guanylate kinase-associated protein (GKAP), localizes at the postsynaptic density (PSD). DLGAP1 knockout mice exhibited alterations of the postsynaptic density and selective reductions in sociability (16). Additionally, previous literatures showed that DLGAP1 is mainly involved in the neuropsychiatric disorders, such as autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and schizophrenia (SCZ).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study of deviated nasal septum using UK Biobank cohort

Liu¹,

Wu²,

Dai³

et al. 2020

Preprint

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Background Deviated nasal septum (DNS) is a common otolaryngology disease. The genetic mechanism underlying DNS remains largely unknown. Methods Totally, 2, 978 DNS patients and 2,978 randomly selected controls from the UK biobank were used in this study. Genotyping was done using the Affymetrix UK BiLEVE Axiom or UK Biobank Axiom array. Genome-wide association study (GWAS) was performed by PLINK 2.0, using age, sex, population structure PC1, PC2 and PC3 as covariates. eQTLs analysis and gene set enrichment analysis (GSEA) were also performed to explore the functional relevance of identified loci with DNS. Results GWAS identified multiple candidate genetic loci for DNS, such as rs75651247 located in DLGAP1 (β=-5.3398, P=9.31×10-8), rs141366706 located in CCND3 (β=-4.7036, P=2.56×10-6), rs76606504 located in FAF1 (β=-4.5013, P=6.76×10-6), and rs142537880 located in SVIL (β= 4.4336, P=9.27×10-6). GSEA detected multiple DNS associated gene sets or pathways, such as KEGG_CALCIUM_SIGNALING_PATHWAY (FDR=3.35×10-3, P=5×10-5) and DAVICIONI_TARGETS_OF_PAX_FOXO1_FUSIONS_UP (FDR=1.60×10-3, P=5×10-5). Conclusions Our study reported multiple candidate genes and gene sets for DNS, providing novel clues for understanding the genetic mechanism of DNS.

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“…Post-synaptic density proteins (PSD) play a critical role in regulating the density and activity of glutamate receptors. As a scaffold protein localized at the PSD of glutamatergic neurons, Dlgap1 knockout leads to disruption of protein interactions in the PSD, and de cits in sociability [38]. And, TANC1 is a PSD-95-interacting synaptic protein that contains multiple domains for protein-protein interactions, important for dendritic spine maintenance and spatial memory [39].…”

Section: Discussionmentioning

confidence: 99%

Intergenerational neurocognitive effects of intrauterine hyperglycemia on male offspring

Zou¹,

Ren²,

Junyu³

et al. 2020

Preprint

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Background Studies on human and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, researches have focused on the neurodevelopment consequences of the first filial (F1) offspring. We hypothesize that the intrauterine hyperglycemia exposure will alter epigenetic reprogramming in F1 sperm, and carry risks of passing on molecular defects to the second filial (F2). Results We found that intrauterine hyperglycemia exposure resulted in memory impairment in both F1 and F2 males from the F1-GDM male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes were enriched in learning, memory, cognition, neurotransmission, synaptic plasticity, and postsynaptic specialization. Again, enrichment curves computed by Gene set enrichment analysis (GSEA) of F1 hippocampi were highly consistent with F2. Interestingly, combined analysis of F1 sperm methylome and gene expression of F2 hippocampi screened out several hypermethylation-low expression genes which are associated with abnormal central nervous system development (particularly synapse development and homeostasis), such as Camk2b, Dlgap1, Wnt5a, Tubb2b and so on. Conclusions These findings implicate that the male germ line is a major player in transgenerational phenotypic transmission. Taken together, our results for the first time suggest that intrauterine hyperglycemia leads to transgenerational cognitive impairment, and, sperm methylome is a potential epigenetic mechanism for the effects of GDM.

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Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability

Cited by 37 publications

References 82 publications

NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models

A genome-wide association study of deviated nasal septum using UK Biobank cohort

Intergenerational neurocognitive effects of intrauterine hyperglycemia on male offspring

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