Htt is a repressor of Abl activity required for APP-induced axonal growth
Autoři:
Claire Marquilly aff001; Germain U. Busto aff001; Brittany S. Leger aff002; Ana Boulanger aff001; Edward Giniger aff003; James A. Walker aff002; Lee G. Fradkin aff006; Jean-Maurice Dura aff001
Působiště autorů:
IGH, Centre National de la Recherche Scientifique, Univ Montpellier, Montpellier, France
aff001; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
aff002; Intramural Research Program, NINDS, NIH, Bethesda, Maryland, United States of America
aff003; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
aff004; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
aff005; Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
aff006
Vyšlo v časopise:
Htt is a repressor of Abl activity required for APP-induced axonal growth. PLoS Genet 17(1): e1009287. doi:10.1371/journal.pgen.1009287
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009287
Souhrn
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 αβ neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αβ 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.
Klíčová slova:
Axons – Cloning – Drosophila melanogaster – Fluorescence resonance energy transfer – Hyperexpression techniques – Larvae – Neurons – Phenotypes
Zdroje
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