Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster.
Animals
Disease Models, Animal
Drosophila Proteins
/ genetics
Drosophila melanogaster
/ genetics
Epistasis, Genetic
/ genetics
Eye
/ metabolism
Gene Knockdown Techniques
HEK293 Cells
Humans
MEF2 Transcription Factors
/ genetics
Myogenic Regulatory Factors
/ genetics
Neurodevelopmental Disorders
/ genetics
Neuroglia
/ metabolism
Phenotype
RNA, Small Interfering
Transfection
Ubiquitin-Protein Ligases
/ genetics
Wings, Animal
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
27 Jan 2020
27 Jan 2020
Historique:
received:
08
09
2019
accepted:
13
01
2020
entrez:
29
1
2020
pubmed:
29
1
2020
medline:
28
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31988313
doi: 10.1038/s41598-020-58182-5
pii: 10.1038/s41598-020-58182-5
pmc: PMC6985129
doi:
Substances chimiques
Drosophila Proteins
0
MEF2 Transcription Factors
0
MEF2C protein, human
0
Mef2 protein, Drosophila
0
Myogenic Regulatory Factors
0
RNA, Small Interfering
0
UBE3A protein, human
EC 2.3.2.26
Ube3a protein, Drosophila
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1204Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : ZW184/1-2
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : ZW184/3-1
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 270949263/GRK2162
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