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.

中文翻译：

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NCBP2调节果蝇和非洲爪蟾模型中3q29缺失的神经发育缺陷。

染色体3q29上1.6 Mbp的缺失与一系列神经发育障碍有关，包括精神分裂症，自闭症，小头畸形和智力障碍。尽管它对神经发育很重要，但单个基因的作用，遗传相互作用和缺失背后的生物学机制尚未得到充分表征。在这里，我们使用定量方法来测定果蝇和非洲爪蟾模型，这些模型具有组织特异性个体和3q29区域内14个同源基因的成对敲除。我们确定了3q29基因的多个同源物的发育，细胞和神经元表型，可能是由于发育过程中细胞凋亡和细胞周期机制的改变。用蝇眼 我们筛选了314个3q29基因同源物的成对敲除，并鉴定了成对同源物之间的44种相互作用以及与其他神经发育基因的34种相互作用。有趣的是，果蝇中的NCBP2同源物（Cbp20）和X. laevis（ncbp2）增强了其他3q29基因的同源物的表型，导致凋亡的显着增加，从而破坏了细胞的组织和大脑形态。这些细胞和神经元缺陷都通过在两种模型中凋亡抑制剂Diap1和xiap的过表达得以挽救，表明凋亡是被缺失破坏的几种潜在生物学机制之一。NCBP2还与人脑特异性相互作用网络中的其他3q29基因高度相关，为我们的结果与人缺失的相关性提供了支持。总体，