Department of Neurobiology
Amino Acids, Peptides, and Proteins | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Neuroscience | Genetics and Genomics | Nervous System Diseases
Huntington's disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer's disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of alphabeta neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB alphabeta neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth.
Axons, Neurons, Cloning, Phenotypes, Fluorescence resonance energy transfer, Drosophila melanogaster, Hyperexpression techniques, Larvae
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DOI of Published Version
Marquilly C, Busto GU, Leger BS, Boulanger A, Giniger E, Walker JA, Fradkin LG, Dura JM. Htt is a repressor of Abl activity required for APP-induced axonal growth. PLoS Genet. 2021 Jan 19;17(1):e1009287. doi: 10.1371/journal.pgen.1009287. PMID: 33465062; PMCID: PMC7845969. Link to article on publisher's site
Marquilly C, Busto GU, Leger BS, Boulanger A, Giniger E, Walker JA, Fradkin LG, Dura J. (2021). Htt is a repressor of Abl activity required for APP-induced axonal growth. Open Access Publications by UMMS Authors. https://doi.org/10.1371/journal.pgen.1009287. Retrieved from https://escholarship.umassmed.edu/oapubs/4563
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