NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA526450 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8707370.fastq.gz | Fastqsanger.gz | |||
| SRR8707380.fastq.gz | Fastqsanger.gz | |||
| SRR8707390.fastq.gz | Fastqsanger.gz | |||
| SRR8707400.fastq.gz | Fastqsanger.gz | |||
| SRR8707410.fastq.gz | Fastqsanger.gz |
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Project description: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.
2019-03-12 | GSE128094 | GEO
Project description:We recently identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental phenotypes, where severely affected probands carried an excess of rare pathogenic variants in the genome compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, but other hits in the genetic background modulate the ultimate phenotypic trajectory. To test this model, we examined the individual contribution of 16p12.1 homologs towards neurodevelopmental, cellular and molecular phenotypes in Drosophila melanogaster and Xenopus laevis. We observed that 16p12.1 homologs affect multiple phenotypic domains, leading to developmental delay, seizure susceptibility, brain size alterations, abnormal neuronal morphology, and cellular proliferation defects. In contrast to genes within CNVs of higher de novo occurrence, such as 16p11.2 deletion, homologs of 16p12.1 genes did not interact with each other, were less connected in a human brain network, and were sensitive to variation in the genetic background. Moreover, 214 “two-hit” models in the fly eye identified additive (47%), suppressive (34.5%), and epistatic (18.5%) interactions between 16p12.1 homologs and 80 homologs of genes carrying “second-hits” in children with the deletion and genes within related neurodevelopmental pathways. In fact, homologs of the intellectual disability-associated “second-hit” gene SETD5 synergistically interacted with homologs of MOSMO, modifying brain and cellular phenotypes and leading to new neuronal defects. Our results provide functional evidence for the “two-hit” model of neurodevelopmental disorders, where multiple 16p12.1 genes sensitize the genome to developmental defects, and complex domain-specific interactions with “second-hit” genes define the final phenotypic manifestation.
2020-05-28 | GSE151330 | GEO
Project description: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.
| S-EPMC7043793 | biostudies-literature
Project description:Xenopus laevis laevis Transcriptome or Gene expression
| PRJNA247381 | ENA