NCBP2modulates neurodevelopmental defects of the 3q29 deletion inDrosophilaandX. laevismodels

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; Rincón-Limas, Diego E.; Lowery, Laura Anne; Girirajan, Santhosh

doi:10.1101/614750

Cited by 3 publications

(13 citation statements)

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“…We previously showed that many of the same fly homologs of CNV genes that showed wing defects in the current study also contributed towards neuronal phenotypes in the fly eye 41, 42 , suggesting a role for these genes in global development. We therefore performed ubiquitous and eye-specific knockdown of fly homologs to assess tissue-specific effects in comparison to the wing phenotypes.…”

Section: Resultssupporting

confidence: 71%

“…We therefore performed ubiquitous and eye-specific knockdown of fly homologs to assess tissue-specific effects in comparison to the wing phenotypes. First, we used the da-GAL4 driver at 25°C to drive ubiquitous knockdown of RNAi lines for 31 homologs of CNV genes, including 19 that were previously published 41, 42 , and observed complete or partial lethality at larval and pupal stages with knockdown of 10/31 homologs (32.3%) ( Fig. 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…To quantitatively assess the phenotypic severity of cellular defects with eye-specific knockdown of fly homologs, we developed a tool called Flynotyper 60 that determines the degree of disorganization among the ommatidia in the adult eye. We analyzed phenotypic scores obtained from Flynotyper for 66 RNAi lines of 45 fly homologs, including from previously-published datasets 41, 42, 60 . We found that 37/45 homologs (82.2%) exhibited both eye and wing-specific defects ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, over 75% of human disease genes have homologs in Drosophila , including many genes involved in cellular signaling processes 39,40 . We recently examined the contributions of individual Drosophila homologs of 28 genes within the 16p11.2 and 3q29 deletion regions towards specific neurodevelopmental phenotypes, including rough eye phenotypes and defects in climbing ability, axon targeting, neuromuscular junction, and dendritic arborization 41, 42 . While these findings implicated multiple genes within each CNV region towards neuronal phenotypes, the conserved role of these genes towards non-neuronal phenotypes is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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

Yusuff

Jensen

Yennawar

et al. 2019

Preprint

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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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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yusuff

Jensen

Yennawar

et al. 2019

Preprint

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“…A recently proposed model to explain phenotypic pleotropism and overlap between different microdeletions is the idea that candidate genes within each microdeleted locus interact with each other through common pathways (Jensen and Girirajan, 2019). This model has received elegant experimental support through Drosophila genetic studies (Iyer et al, 2018;Singh et al, 2019;Yusuff et al, 2019). Our findings support this idea with genetic and biochemical interactions between human and Drosophila orthologues of SLC25A1 and MRPL40.…”

Section: Discussionsupporting

confidence: 76%

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus that are Necessary for Synapse Function

Gokhale

Lee

Zlatic

et al. 2020

Preprint

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Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in this microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial protein translation and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a novel pathogenic mechanism for neurodevelopmental disorders.

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Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus

et al. 2021

View full text Add to dashboard Cite

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.

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NCBP2modulates neurodevelopmental defects of the 3q29 deletion inDrosophilaandX. laevismodels

Cited by 3 publications

References 128 publications

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

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

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus that are Necessary for Synapse Function

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus

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