title: Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/β-catenin pathway in a Drosophila model for intellectual disability.
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.
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium ; Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Vandewalle
authors.forename: Marion
authors.initials: M
authors.lastname: Langen
authors.forename: Marlen
authors.initials: M
authors.lastname: Zschätzsch
authors.forename: Marlen
authors.initials: M
authors.lastname: Zschaetzsch
authors.forename: Bonnie
authors.initials: B
authors.lastname: Nijhof
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Kramer
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
authors.forename: Marijke
authors.initials: M
authors.lastname: Bauters
authors.forename: Elsa
authors.initials: E
authors.lastname: Lauwers
authors.forename: Mohammed
authors.initials: M
authors.lastname: Srahna
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D015870:Gene Expression; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007858:Learning; D008568:Memory; D024521:Mushroom Bodies / Q000378:metabolism / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009435:Synaptic Transmission; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D025521:Tumor Suppressor Proteins; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases