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

English version

Autoři: Tanzeen Yusuff ^aff001; Matthew Jensen ^aff001; Sneha Yennawar ^aff001; Lucilla Pizzo ^aff001; Siddharth Karthikeyan ^aff001; Dagny J. Gould ^aff001; Avik Sarker ^aff001; Erika Gedvilaite ^aff001; Yurika Matsui ^aff001; Janani Iyer ^aff001; Zhi-Chun Lai ^aff001; 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, Pennsylvania State University, University Park, Pennsylvania, United States of America ^aff002; Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America ^aff003
Vyšlo v časopise: Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008792
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008792

Souhrn

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.

Klíčová slova:

Apoptosis – Drosophila melanogaster – Eyes – Genetic networks – Hedgehog signaling – Notch signaling – Phenotypes – RNA interference

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Článek Integrins regulate epithelial cell shape by controlling the architecture and mechanical properties of basal actomyosin networks

Článek Cancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism

Článek NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure

Článek Pax6 organizes the anterior eye segment by guiding two distinct neural crest waves

Článek Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

Článek Identification of Clec4b as a novel regulator of bystander activation of auto-reactive T cells and autoimmune disease