A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

Nielsen, Jacob; Fejgin, Kim; Sotty, Florence; Nielsen, Vibeke; Mørk, Arne; Christoffersen, Claus T.; Yavich, Leonid; Lauridsen, Jes B.; Clausen, Dorte; Larsen, Peter H.; Egebjerg, Jan; Werge, Thomas; Kallunki, Pekka; Christensen, Kenneth Vielsted; Didriksen, Michael

doi:10.1038/s41398-017-0011-8

Cited by 40 publications

(41 citation statements)

References 44 publications

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“…Even highly related cell populations have too many differences to be followed up, especially if it is considered that also non-coding variants may play important roles. From disease biology it is well-known that mild (no full loss of any gene) copy number variation can have pronounced effects, and the gene combinations responsible for such effects have been hard to define (Nielsen et al 2017 ). Our findings, together with these background considerations, suggest that targeted testing, related to the specific functional demands of cells in a given study, is required.…”

Section: Discussionmentioning

confidence: 99%

Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift

et al. 2018

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Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyridinium (MPP+) were observed. Whole-genome sequencing was performed to identify underlying genetic differences. While both SP had normal chromosome structures, they displayed about 70 differences on the level of amino acid changing events. Some of these differences were confirmed biochemically, but none offered a direct explanation for the altered toxicant sensitivity pattern. As second approach, markers known to be relevant for the intended use of the cells were specifically tested. The “ATCC” cells rapidly down-regulated the dopamine-transporter and tyrosine-hydroxylase after differentiation, while “UKN” cells maintained functional levels. As the respective genes were not altered themselves, we conclude that polygenic complex upstream changes can have drastic effects on biochemical features and toxicological responses of relatively similar SP of cells.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2326-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift

et al. 2018

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“…Data 3 ). For example, both homologs of genes within 1q21.1 region, BCL9 / lgs and FMO5/Fmo-2 , showed decreased wing area and vein length, potentially mirroring the reduced body length phenotype observed in mouse models of the deletion 56 ( Fig. 4B-C ).…”

Section: Resultsmentioning

confidence: 81%

Drosophilamodels of pathogenic copy-number variant genes show global and non-neuronal defects during development

Yusuff

Jensen

Yennawar

et al. 2019

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24While rare pathogenic CNVs are associated with both neuronal and non-neuronal phenotypes, 25 functional studies evaluating these regions have focused on the molecular basis of neuronal 26 defects. We report a systematic functional analysis of non-neuronal phenotypes for 59 homologs 27 of genes within ten CNVs and 20 neurodevelopmental genes in Drosophila. Using wing-specific 28 knockdown of 136 RNA interference lines, we identify phenotypes in 72/79 homologs including 29 six lines with lethality and 21 lines with severe phenotypes. We find no correlation between 30 severity of these phenotypes and neuronal defects due to eye-specific knockdown. We observe 31 disruptions in cell proliferation and apoptosis for 23/27 homologs, and altered Wnt, Hedgehog 32 and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and 33 KIF11/Klp61F, validated with differences in human tissue-specific expression and network 34 connectivity. Our findings suggest that multiple genes within each CNV differentially affect both 35 global and tissue-specific developmental processes, contributing to non-neuronal phenotypes of 36 CNV disorders. 37 38 39 40Rare copy-number variants (CNVs), or deletions and duplications in the genome, are associated 41 with neurodevelopmental disorders such as autism, intellectual disability (ID), and 42 schizophrenia 1,2 . While dosage alteration of CNV regions contribute predominantly to defects in 43 nervous system development, several CNV disorders also lead to early developmental features 44 involving other organ systems 3,4 , including cardiac defects 5,6 , kidney malformations 7 , 45 craniofacial features 3 , and skeletal abnormalities 8 . In fact, an overall survey of ten rare disease-46 associated CNVs among individuals within the DECIPHER database 9 showed a wide range of 47 non-neuronal phenotypes across multiple organ systems for each CNV disorder ( Fig. 1). For 48 example, the 1q21.1 deletion causes variable expression of multiple neuronal and non-neuronal 49 phenotypes, including developmental delay, autism, and schizophrenia as well as craniofacial 50 features, cataracts, cardiac defects, and skeletal abnormalities 10-12 . Additionally, while the 51 7q11.23 deletion associated with Williams-Beuren syndrome (WBS) causes neuropsychiatric and 52 behavioral features, other non-neuronal phenotypes, including supravalvular aortic stenosis, 53 auditory defects, hypertension, diabetes mellitus, and musculoskeletal and connective tissue 54 anomalies, are also observed among the deletion carriers 13 . In fact, individual genes within the 55 WBS region are associated with specific features of the deletion, such as ELN and supravalvular 56 aortic stenosis 14 , STX1A and impaired glucose tolerance 15 , LIMK1 and impaired visuospatial 57 abilities 16 , and GTF2IRD1 and craniofacial abnormalities 17 . Furthermore, TBX1 was identified to 58 cause the pharyngeal arch cardiac defects associated with the 22q11.2 deletion (DiGeorge 59 syndrome) 18 , while HNF1B within the 17q12 delet...

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“…showed smaller wing areas and five homologs showed larger wing areas compared to controls (S4 Data). For example, both homologs of genes within 1q21.1 region, BCL9/lgs and FMO5/ Fmo-2, showed decreased wing area and vein length, potentially mirroring the reduced body length phenotype observed in mouse models of the deletion [45] (Fig 4B and 4C). In addition, PAK2/Pak within 3q29, TBX1/org-1 within 22q11.2, autism-associated CHD8/kis, and microcephaly-associated ASPM/asp also showed smaller wing areas and vein lengths (Fig 4B and 4C).…”

Section: Plos Geneticsmentioning

confidence: 82%

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development

et al. 2020

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While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

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A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

Cited by 40 publications

References 44 publications

Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift

Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift

Drosophilamodels of pathogenic copy-number variant genes show global and non-neuronal defects during development

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development

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