Sorting nexin 3 mutation impairs development and neuronal function in Caenorhabditis elegans
The sorting nexins family of proteins (SNXs) plays pleiotropic functions in protein trafficking and intracellular signaling and has been associated with several disorders, namely Alzheimer’s disease and Down’s syndrome. Despite the growing association of SNXs with neurodegeneration, not much is known about their function in the nervous system. The aim of this work was to use the nematode Caenorhabditis elegans that encodes in its genome eight SNXs orthologs, to dissect the role of distinct SNXs, particularly in the nervous system. By screening the C. elegans SNXs deletion mutants for morphological, developmental and behavioral alterations, we show here that snx-3 gene mutation leads to an array of developmental defects, such as delayed hatching, decreased brood size and life span and reduced body length. Additionally, ∆snx-3 worms present increased susceptibility to osmotic, thermo and oxidative stress and distinct behavioral deficits, namely, a chemotaxis defect which is independent of the described snx-3 role in Wnt secretion. ∆snx-3 animals also display abnormal GABAergic neuronal architecture and wiring and altered AIY interneuron structure. Pan-neuronal expression of C. elegans snx-3 cDNA in the ∆snx-3 mutant is able to rescue its locomotion defects, as well as its chemotaxis toward isoamyl alcohol. Altogether, the present work provides the first in vivo evidence of the SNX-3 role in the nervous system.
KeywordsBehavior Neuronal defects Impaired development Nervous system Sorting nexins
This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the Project POCI-01-0145-FEDER-007038; and by a 2016 NARSAD Young Investigator Grant (#24929) from the Brain and Behavior Research Foundation. This work was developed under the scope of the Project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). NV is supported by the FCT Fellowship SFRH/BPD/91250/2012. AJR is an FCT Investigator IF/00883/2013. CB is supported by a FCT Grant SFRH/BPD/74452/2010 (POPH/FS). PM is supported by a fellowship from the project “Envelhecimento cognitivo saudável–proporcionar saúde mental no processo biológico do envelhecimento” (Contract P-139977) funded by Calouste Gulbenkian–Inovar em Saúde. Research in AXC’s lab is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Grant agreement 640553-ACTOMYO). AXC has a FCT Investigator position funded by FCT and co-funded by the European Social Fund through Programa Operacional Temático Potencial Type 4.2 promotion of scientific employment. FC is supported by the FCT fellowship SFRH/BPD/93528/2013. We would like to thank all the members of the NeRD research domain, ICVS, for fruitful discussion and advices.
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Conflict of interest
The authors declare that they have no conflict of interest.
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