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PLoS Genet 2020 Feb 13;162:e1008590. doi: 10.1371/journal.pgen.1008590.
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NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models.

Singh MD , Jensen M , Lasser M , Huber E , Yusuff T , Pizzo L , Lifschutz B , Desai I , Kubina A , Yennawar S , Kim S , Iyer J , Rincon-Limas DE , Lowery LA , Girirajan S .

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.

PubMed ID: 32053595
PMC ID: PMC7043793
Article link: PLoS Genet
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: dcp1b dlg1 fbxo45 lgals4.2 ncbp2 pak2 slc51a xiap
GO keywords: eye development [+]
Antibodies: Casp3 Ab1 Tuba4b Ab16
Morpholinos: dlg1 MO2 fbxo45 MO1 ncbp2 MO1 pak2 MO1

Disease Ontology terms: autism spectrum disorder [+]
Phenotypes: Xla Wt + fbxo45 MO (Table 1, Fig. 8 A B C) [+]

Article Images: [+] show captions
References [+] :
Abrahams, SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). 2013, Pubmed