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Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability

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 developi...

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Autores principales: Vandewalle, Joke, Langen, Marion, Zschaetzsch, Marlen, Nijhof, Bonnie, Kramer, Jamie M., Brems, Hilde, Bauters, Marijke, Lauwers, Elsa, Srahna, Mohammed, Marynen, Peter, Verstreken, Patrik, Schenck, Annette, Hassan, Bassem A., Froyen, Guy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841167/
https://www.ncbi.nlm.nih.gov/pubmed/24303071
http://dx.doi.org/10.1371/journal.pone.0081791
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author Vandewalle, Joke
Langen, Marion
Zschaetzsch, Marlen
Nijhof, Bonnie
Kramer, Jamie M.
Brems, Hilde
Bauters, Marijke
Lauwers, Elsa
Srahna, Mohammed
Marynen, Peter
Verstreken, Patrik
Schenck, Annette
Hassan, Bassem A.
Froyen, Guy
author_facet Vandewalle, Joke
Langen, Marion
Zschaetzsch, Marlen
Nijhof, Bonnie
Kramer, Jamie M.
Brems, Hilde
Bauters, Marijke
Lauwers, Elsa
Srahna, Mohammed
Marynen, Peter
Verstreken, Patrik
Schenck, Annette
Hassan, Bassem A.
Froyen, Guy
author_sort Vandewalle, Joke
collection PubMed
description 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.
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spelling pubmed-38411672013-12-03 Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability Vandewalle, Joke Langen, Marion Zschaetzsch, Marlen Nijhof, Bonnie Kramer, Jamie M. Brems, Hilde Bauters, Marijke Lauwers, Elsa Srahna, Mohammed Marynen, Peter Verstreken, Patrik Schenck, Annette Hassan, Bassem A. Froyen, Guy PLoS One Research Article 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. Public Library of Science 2013-11-26 /pmc/articles/PMC3841167/ /pubmed/24303071 http://dx.doi.org/10.1371/journal.pone.0081791 Text en © 2013 Vandewalle et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vandewalle, Joke
Langen, Marion
Zschaetzsch, Marlen
Nijhof, Bonnie
Kramer, Jamie M.
Brems, Hilde
Bauters, Marijke
Lauwers, Elsa
Srahna, Mohammed
Marynen, Peter
Verstreken, Patrik
Schenck, Annette
Hassan, Bassem A.
Froyen, Guy
Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability
title Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability
title_full Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability
title_fullStr Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability
title_full_unstemmed Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability
title_short Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/β-Catenin Pathway in a Drosophila Model for Intellectual Disability
title_sort ubiquitin ligase huwe1 regulates axon branching through the wnt/β-catenin pathway in a drosophila model for intellectual disability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841167/
https://www.ncbi.nlm.nih.gov/pubmed/24303071
http://dx.doi.org/10.1371/journal.pone.0081791
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