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


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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Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

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