NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models
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 biologica...
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| creator | Singh, Mayanglambam Dhruba Jensen, Matthew Lasser, Micaela Huber, Emily Yusuff, Tanzeen Pizzo, Lucilla Lifschutz, Brian Desai, Inshya Kubina, Alexis Yennawar, Sneha Kim, Sydney Iyer, Janani Rincon-Limas, Diego E Lowery, Laura Anne Girirajan, Santhosh |
| 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. |
| doi_str_mv | 10.1371/journal.pgen.1008590 |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1008590</identifier><identifier>PMID: 32053595</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animals ; Apoptosis ; Apoptosis - genetics ; Autism ; Biochemistry ; Biology and Life Sciences ; Brain ; Brain - embryology ; Brain - pathology ; Brain architecture ; Cell cycle ; Cell Cycle - genetics ; Chromosome 3 ; Chromosome Deletion ; Chromosomes, Human, Pair 3 - genetics ; Clonal deletion ; Defects ; Developmental Disabilities - genetics ; Developmental Disabilities - pathology ; Disabilities ; Disease Models, Animal ; Drosophila ; Drosophila melanogaster ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Embryo, Nonmammalian ; Embryonic Development - genetics ; Female ; Gene expression ; Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Gene Regulatory Networks ; Genes ; Genetic aspects ; Genetic engineering ; Humans ; Insects ; Intellectual disabilities ; Intellectual Disability - genetics ; Intellectual Disability - pathology ; Medicine and Health Sciences ; Mental disorders ; Microencephaly ; Molecular biology ; Neurodevelopmental disorders ; Neurons ; Neurophysiology ; Nuclear Cap-Binding Protein Complex - genetics ; Nuclear Cap-Binding Protein Complex - metabolism ; Phenotypes ; Research and Analysis Methods ; Schizophrenia ; Supervision ; Xenopus laevis ; Xenopus Proteins - genetics ; Xenopus Proteins - metabolism ; XIAP protein</subject><ispartof>PLoS genetics, 2020-02, Vol.16 (2), p.e1008590</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Singh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Singh et al 2020 Singh et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c726t-6b587c8a59f3c38bce2e66900db153191aa7307e090424951da21308d029998e3</citedby><cites>FETCH-LOGICAL-c726t-6b587c8a59f3c38bce2e66900db153191aa7307e090424951da21308d029998e3</cites><orcidid>0000-0003-0598-4945 ; 0000-0003-0123-7141 ; 0000-0003-2419-5888 ; 0000-0003-0666-9744 ; 0000-0003-3099-0642 ; 0000-0001-8959-2679 ; 0000-0002-5601-9208 ; 0000-0002-5153-8543 ; 0000-0001-9325-7283 ; 0000-0002-9730-6094</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043793/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043793/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32053595$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Mayanglambam Dhruba</creatorcontrib><creatorcontrib>Jensen, Matthew</creatorcontrib><creatorcontrib>Lasser, Micaela</creatorcontrib><creatorcontrib>Huber, Emily</creatorcontrib><creatorcontrib>Yusuff, Tanzeen</creatorcontrib><creatorcontrib>Pizzo, Lucilla</creatorcontrib><creatorcontrib>Lifschutz, Brian</creatorcontrib><creatorcontrib>Desai, Inshya</creatorcontrib><creatorcontrib>Kubina, Alexis</creatorcontrib><creatorcontrib>Yennawar, Sneha</creatorcontrib><creatorcontrib>Kim, Sydney</creatorcontrib><creatorcontrib>Iyer, Janani</creatorcontrib><creatorcontrib>Rincon-Limas, Diego E</creatorcontrib><creatorcontrib>Lowery, Laura Anne</creatorcontrib><creatorcontrib>Girirajan, Santhosh</creatorcontrib><title>NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><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.</description><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Autism</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Brain</subject><subject>Brain - embryology</subject><subject>Brain - pathology</subject><subject>Brain architecture</subject><subject>Cell cycle</subject><subject>Cell Cycle - genetics</subject><subject>Chromosome 3</subject><subject>Chromosome Deletion</subject><subject>Chromosomes, Human, Pair 3 - genetics</subject><subject>Clonal deletion</subject><subject>Defects</subject><subject>Developmental Disabilities - genetics</subject><subject>Developmental Disabilities - pathology</subject><subject>Disabilities</subject><subject>Disease Models, Animal</subject><subject>Drosophila</subject><subject>Drosophila melanogaster</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Embryo, Nonmammalian</subject><subject>Embryonic Development - genetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Gene Knockdown Techniques</subject><subject>Gene Regulatory Networks</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Humans</subject><subject>Insects</subject><subject>Intellectual disabilities</subject><subject>Intellectual Disability - genetics</subject><subject>Intellectual Disability - pathology</subject><subject>Medicine and Health Sciences</subject><subject>Mental disorders</subject><subject>Microencephaly</subject><subject>Molecular biology</subject><subject>Neurodevelopmental disorders</subject><subject>Neurons</subject><subject>Neurophysiology</subject><subject>Nuclear Cap-Binding Protein Complex - genetics</subject><subject>Nuclear Cap-Binding Protein Complex - metabolism</subject><subject>Phenotypes</subject><subject>Research and Analysis Methods</subject><subject>Schizophrenia</subject><subject>Supervision</subject><subject>Xenopus laevis</subject><subject>Xenopus Proteins - genetics</subject><subject>Xenopus Proteins - metabolism</subject><subject>XIAP 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modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models</title><author>Singh, Mayanglambam Dhruba ; Jensen, Matthew ; Lasser, Micaela ; Huber, Emily ; Yusuff, Tanzeen ; Pizzo, Lucilla ; Lifschutz, Brian ; Desai, Inshya ; Kubina, Alexis ; Yennawar, Sneha ; Kim, Sydney ; Iyer, Janani ; Rincon-Limas, Diego E ; Lowery, Laura Anne ; Girirajan, Santhosh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c726t-6b587c8a59f3c38bce2e66900db153191aa7307e090424951da21308d029998e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Autism</topic><topic>Biochemistry</topic><topic>Biology and Life Sciences</topic><topic>Brain</topic><topic>Brain - embryology</topic><topic>Brain - pathology</topic><topic>Brain architecture</topic><topic>Cell cycle</topic><topic>Cell Cycle - genetics</topic><topic>Chromosome 3</topic><topic>Chromosome Deletion</topic><topic>Chromosomes, Human, Pair 3 - genetics</topic><topic>Clonal deletion</topic><topic>Defects</topic><topic>Developmental Disabilities - genetics</topic><topic>Developmental Disabilities - pathology</topic><topic>Disabilities</topic><topic>Disease Models, Animal</topic><topic>Drosophila</topic><topic>Drosophila melanogaster</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - metabolism</topic><topic>Embryo, Nonmammalian</topic><topic>Embryonic Development - genetics</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Gene Knockdown Techniques</topic><topic>Gene Regulatory Networks</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic engineering</topic><topic>Humans</topic><topic>Insects</topic><topic>Intellectual disabilities</topic><topic>Intellectual Disability - genetics</topic><topic>Intellectual Disability - pathology</topic><topic>Medicine and Health Sciences</topic><topic>Mental disorders</topic><topic>Microencephaly</topic><topic>Molecular biology</topic><topic>Neurodevelopmental disorders</topic><topic>Neurons</topic><topic>Neurophysiology</topic><topic>Nuclear Cap-Binding Protein Complex - genetics</topic><topic>Nuclear Cap-Binding Protein Complex - metabolism</topic><topic>Phenotypes</topic><topic>Research and Analysis Methods</topic><topic>Schizophrenia</topic><topic>Supervision</topic><topic>Xenopus laevis</topic><topic>Xenopus Proteins - genetics</topic><topic>Xenopus Proteins - metabolism</topic><topic>XIAP protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Mayanglambam Dhruba</creatorcontrib><creatorcontrib>Jensen, Matthew</creatorcontrib><creatorcontrib>Lasser, Micaela</creatorcontrib><creatorcontrib>Huber, Emily</creatorcontrib><creatorcontrib>Yusuff, 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Santhosh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2020-02-13</date><risdate>2020</risdate><volume>16</volume><issue>2</issue><spage>e1008590</spage><pages>e1008590-</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32053595</pmid><doi>10.1371/journal.pgen.1008590</doi><orcidid>https://orcid.org/0000-0003-0598-4945</orcidid><orcidid>https://orcid.org/0000-0003-0123-7141</orcidid><orcidid>https://orcid.org/0000-0003-2419-5888</orcidid><orcidid>https://orcid.org/0000-0003-0666-9744</orcidid><orcidid>https://orcid.org/0000-0003-3099-0642</orcidid><orcidid>https://orcid.org/0000-0001-8959-2679</orcidid><orcidid>https://orcid.org/0000-0002-5601-9208</orcidid><orcidid>https://orcid.org/0000-0002-5153-8543</orcidid><orcidid>https://orcid.org/0000-0001-9325-7283</orcidid><orcidid>https://orcid.org/0000-0002-9730-6094</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2020-02, Vol.16 (2), p.e1008590 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_2377705539 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Analysis Animals Apoptosis Apoptosis - genetics Autism Biochemistry Biology and Life Sciences Brain Brain - embryology Brain - pathology Brain architecture Cell cycle Cell Cycle - genetics Chromosome 3 Chromosome Deletion Chromosomes, Human, Pair 3 - genetics Clonal deletion Defects Developmental Disabilities - genetics Developmental Disabilities - pathology Disabilities Disease Models, Animal Drosophila Drosophila melanogaster Drosophila Proteins - genetics Drosophila Proteins - metabolism Embryo, Nonmammalian Embryonic Development - genetics Female Gene expression Gene Expression Regulation, Developmental Gene Knockdown Techniques Gene Regulatory Networks Genes Genetic aspects Genetic engineering Humans Insects Intellectual disabilities Intellectual Disability - genetics Intellectual Disability - pathology Medicine and Health Sciences Mental disorders Microencephaly Molecular biology Neurodevelopmental disorders Neurons Neurophysiology Nuclear Cap-Binding Protein Complex - genetics Nuclear Cap-Binding Protein Complex - metabolism Phenotypes Research and Analysis Methods Schizophrenia Supervision Xenopus laevis Xenopus Proteins - genetics Xenopus Proteins - metabolism XIAP protein |
| title | NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T01%3A20%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=NCBP2%20modulates%20neurodevelopmental%20defects%20of%20the%203q29%20deletion%20in%20Drosophila%20and%20Xenopus%20laevis%20models&rft.jtitle=PLoS%20genetics&rft.au=Singh,%20Mayanglambam%20Dhruba&rft.date=2020-02-13&rft.volume=16&rft.issue=2&rft.spage=e1008590&rft.pages=e1008590-&rft.issn=1553-7404&rft.eissn=1553-7404&rft_id=info:doi/10.1371/journal.pgen.1008590&rft_dat=%3Cgale_plos_%3EA616216550%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2377705539&rft_id=info:pmid/32053595&rft_galeid=A616216550&rft_doaj_id=oai_doaj_org_article_70c2a6475aa74212a798ae4353e5a86f&rfr_iscdi=true |