Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster
| Autor: | Straub, Jonas, Gregor, Anne, Sauerer, Tatjana, Fliedner, Anna, Distel, Laila, Suchy, Christine, Ekici, Arif B., Ferrazzi, Fulvia, Zweier, Christiane |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Ubiquitin-Protein Ligases lcsh:Medicine Eye Transfection Article Medizinische Fakultät Animals Drosophila Proteins Humans Wings Animal ddc:610 RNA Small Interfering lcsh:Science Molecular medicine MEF2 Transcription Factors Genetic interaction Medical genetics Neurodevelopmental disorders lcsh:R Epistasis Genetic Disease Models Animal Drosophila melanogaster HEK293 Cells Phenotype Myogenic Regulatory Factors Gene Knockdown Techniques lcsh:Q Neuroglia |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) Publons Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-58182-5 |
| Popis: | Neurodevelopmental disorders (NDDs) are clinically and genetically extremely heterogeneous with shared phenotypes often associated with genes from the same networks. Mutations in TCF4, MEF2C, UBE3A, ZEB2 or ATRX cause phenotypically overlapping, syndromic forms of NDDs with severe intellectual disability, epilepsy and microcephaly. To characterize potential functional links between these genes/proteins, we screened for genetic interactions in Drosophila melanogaster. We induced ubiquitous or tissue specific knockdown or overexpression of each single orthologous gene (Da, Mef2, Ube3a, Zfh1, XNP) and in pairwise combinations. Subsequently, we assessed parameters such as lethality, wing and eye morphology, neuromuscular junction morphology, bang sensitivity and climbing behaviour in comparison between single and pairwise dosage manipulations. We found most stringent evidence for genetic interaction between Ube3a and Mef2 as simultaneous dosage manipulation in different tissues including glia, wing and eye resulted in multiple phenotype modifications. We subsequently found evidence for physical interaction between UBE3A and MEF2C also in human cells. Systematic pairwise assessment of the Drosophila orthologues of five genes implicated in clinically overlapping, severe NDDs and subsequent confirmation in a human cell line revealed interactions between UBE3A/Ube3a and MEF2C/Mef2, thus contributing to the characterization of the underlying molecular commonalities. |
| Databáze: | OpenAIRE |
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