Abstract
We recently reported that duplication of the E3 ubiquitin ligase HUWE1 results in intellectual disability (ID) in male patients. However, the underlying molecular mechanism remains unknown. We used Drosophila melanogaster as a model to investigate the effect of increased HUWE1 levels on the developing nervous system. Similar to the observed levels in patients we overexpressed the HUWE1 mRNA about 2-fold in the fly. The development of the mushroom body and neuromuscular junctions were not altered, and basal neurotransmission was unaffected. These data are in agreement with normal learning and memory in the courtship conditioning paradigm. However, a disturbed branching phenotype at the axon terminals of the dorsal cluster neurons (DCN) was detected. Interestingly, overexpression of HUWE1 was found to decrease the protein levels of dishevelled (dsh) by 50%. As dsh as well as Fz2 mutant flies showed the same disturbed DCN branching phenotype, and the constitutive active homolog of β-catenin, armadillo, could partially rescue this phenotype, our data strongly suggest that increased dosage of HUWE1 compromises the Wnt/β-catenin pathway possibly by enhancing the degradation of dsh.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Axons / metabolism*
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Disease Models, Animal
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Drosophila
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Gene Expression
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Humans
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Intellectual Disability / genetics
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Intellectual Disability / metabolism*
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Intellectual Disability / physiopathology
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Learning
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Memory
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Mushroom Bodies / metabolism
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Mushroom Bodies / physiopathology
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Neuromuscular Junction / metabolism
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Neurons / metabolism
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Synaptic Transmission
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Tumor Suppressor Proteins
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Ubiquitin-Protein Ligases / metabolism*
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Wnt Signaling Pathway*
Substances
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Tumor Suppressor Proteins
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HUWE1 protein, human
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Ubiquitin-Protein Ligases
Grants and funding
This work was supported by VIB to BAH and GF, the GOA/12/015 grant of the University of Leuven (KU Leuven, Belgium) to GF, FWO grants G.0679.10, G.0680.10, G.0681.10 and G.0682.10 to BAH, the European Union under the 7th framework program (Gencodys HEALTH-F4-2010-241995) and by a Vidi grant from the Netherlands Organization for Health Research and Development (ZonMw 917-96-346) to AS. JV is a PhD fellow from the IWT (Agentschap voor Innovatie door Wetenschap en Technologie), Belgium. MB is a post-doctoral fellow of the FWO-Vlaanderen, Belgium. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.