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

Autoři: Mayanglambam Dhruba Singh aff001;  Matthew Jensen aff001;  Micaela Lasser aff002;  Emily Huber aff001;  Tanzeen Yusuff aff001;  Lucilla Pizzo aff001;  Brian Lifschutz aff001;  Inshya Desai aff001;  Alexis Kubina aff001;  Sneha Yennawar aff001;  Sydney Kim aff002;  Janani Iyer aff001;  Diego E. Rincon-Limas aff003;  Laura Anne Lowery aff002;  Santhosh Girirajan aff001
Působiště autorů: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff001;  Department of Biology, Boston College, Chestnut Hill, Massachusetts, United States of America aff002;  Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America aff003;  Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff004;  Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States of America aff004;  Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff005
Vyšlo v časopise: NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008590
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008590


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.

Klíčová slova:

Apoptosis – Cell staining – Drosophila melanogaster – Eyes – Hyperexpression techniques – Phenotypes – RNA interference – Xenopus


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