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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| creator | Vandewalle, Joke Langen, Marion Zschätzsch, Marlen 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 |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0081791 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0081791</identifier><identifier>PMID: 24303071</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer's disease ; Animals ; Animals, Genetically Modified ; Axons - metabolism ; Biology ; Cell cycle ; Cognition & reasoning ; Cognitive ability ; Courtship ; Disease Models, Animal ; Dishevelled protein ; Drosophila ; Gene Expression ; Genes ; Genetics ; Genomes ; Homology ; Humans ; Huwe1 protein ; Insects ; Intellectual disabilities ; Intellectual Disability - genetics ; Intellectual Disability - metabolism ; Intellectual Disability - physiopathology ; Laboratories ; Learning ; Life sciences ; Memory ; mRNA ; Mushroom Bodies - metabolism ; Mushroom Bodies - physiopathology ; Nervous system ; Neuromuscular Junction - metabolism ; Neuromuscular junctions ; Neurons - metabolism ; Neurotransmission ; Patients ; Presynapse ; Studies ; Synaptic Transmission ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - metabolism ; Wnt protein ; Wnt Signaling Pathway ; β-Catenin</subject><ispartof>PloS one, 2013-11, Vol.8 (11), p.e81791-e81791</ispartof><rights>2013 Vandewalle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Vandewalle et al 2013 Vandewalle et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-d42d843192ee2db203a48280ff0b2e4e97920f2b3f87ffc8bc37d8b9c0e244093</citedby><cites>FETCH-LOGICAL-c526t-d42d843192ee2db203a48280ff0b2e4e97920f2b3f87ffc8bc37d8b9c0e244093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841167/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841167/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24303071$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vandewalle, Joke</creatorcontrib><creatorcontrib>Langen, Marion</creatorcontrib><creatorcontrib>Zschätzsch, Marlen</creatorcontrib><creatorcontrib>Zschaetzsch, Marlen</creatorcontrib><creatorcontrib>Nijhof, Bonnie</creatorcontrib><creatorcontrib>Kramer, Jamie M</creatorcontrib><creatorcontrib>Brems, Hilde</creatorcontrib><creatorcontrib>Bauters, Marijke</creatorcontrib><creatorcontrib>Lauwers, Elsa</creatorcontrib><creatorcontrib>Srahna, Mohammed</creatorcontrib><creatorcontrib>Marynen, Peter</creatorcontrib><creatorcontrib>Verstreken, Patrik</creatorcontrib><creatorcontrib>Schenck, Annette</creatorcontrib><creatorcontrib>Hassan, Bassem A</creatorcontrib><creatorcontrib>Froyen, Guy</creatorcontrib><title>Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/β-catenin pathway in a Drosophila model for intellectual disability</title><title>PloS one</title><addtitle>PLoS One</addtitle><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.</description><subject>Alzheimer's disease</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Axons - metabolism</subject><subject>Biology</subject><subject>Cell cycle</subject><subject>Cognition & reasoning</subject><subject>Cognitive ability</subject><subject>Courtship</subject><subject>Disease Models, Animal</subject><subject>Dishevelled protein</subject><subject>Drosophila</subject><subject>Gene Expression</subject><subject>Genes</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Homology</subject><subject>Humans</subject><subject>Huwe1 protein</subject><subject>Insects</subject><subject>Intellectual disabilities</subject><subject>Intellectual Disability - 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metabolism</topic><topic>Biology</topic><topic>Cell cycle</topic><topic>Cognition & reasoning</topic><topic>Cognitive ability</topic><topic>Courtship</topic><topic>Disease Models, Animal</topic><topic>Dishevelled protein</topic><topic>Drosophila</topic><topic>Gene Expression</topic><topic>Genes</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Homology</topic><topic>Humans</topic><topic>Huwe1 protein</topic><topic>Insects</topic><topic>Intellectual disabilities</topic><topic>Intellectual Disability - genetics</topic><topic>Intellectual Disability - metabolism</topic><topic>Intellectual Disability - physiopathology</topic><topic>Laboratories</topic><topic>Learning</topic><topic>Life sciences</topic><topic>Memory</topic><topic>mRNA</topic><topic>Mushroom Bodies - metabolism</topic><topic>Mushroom Bodies - physiopathology</topic><topic>Nervous system</topic><topic>Neuromuscular Junction - metabolism</topic><topic>Neuromuscular junctions</topic><topic>Neurons - metabolism</topic><topic>Neurotransmission</topic><topic>Patients</topic><topic>Presynapse</topic><topic>Studies</topic><topic>Synaptic Transmission</topic><topic>Ubiquitin</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitin-Protein Ligases - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24303071</pmid><doi>10.1371/journal.pone.0081791</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Alzheimer's disease Animals Animals, Genetically Modified Axons - metabolism Biology Cell cycle Cognition & reasoning Cognitive ability Courtship Disease Models, Animal Dishevelled protein Drosophila Gene Expression Genes Genetics Genomes Homology Humans Huwe1 protein Insects Intellectual disabilities Intellectual Disability - genetics Intellectual Disability - metabolism Intellectual Disability - physiopathology Laboratories Learning Life sciences Memory mRNA Mushroom Bodies - metabolism Mushroom Bodies - physiopathology Nervous system Neuromuscular Junction - metabolism Neuromuscular junctions Neurons - metabolism Neurotransmission Patients Presynapse Studies Synaptic Transmission Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - metabolism Wnt protein Wnt Signaling Pathway β-Catenin |
| title | Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/β-catenin pathway in a Drosophila model for intellectual disability |
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