title: Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.
abstract: Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury we found mitochondrial fission in dendrites was upregulated, and that reducing fission increased stabilization or neuroprotection (NP). Thus axon injury seems to both turn on NP, but also dampen it by activating mitochondrial fission. We also identified caspases as negative regulators of axon injury-mediated NP, so mitochondrial fission could control NP through caspase activation. In addition to negative regulators of NP, we found that nicotinamide mononucleotide adenylyltransferase (Nmnat) is absolutely required for this type of NP. Increased microtubule dynamics, which has previously been associated with NP, required Nmnat. Indeed Nmnat overexpression was sufficient to induce NP and increase microtubule dynamics in the absence of axon injury. DLK, JNK and fos were also required for NP. Because NP occurs before axon regeneration, and NP seems to be actively downregulated, we tested whether excessive NP might inhibit regeneration. Indeed both Nmnat overexpression and caspase reduction reduced regeneration. In addition, overexpression of fos or JNK extended the timecourse of NP and dampened regeneration in a Nmnat-dependent manner. These data suggest that NP and regeneration are conflicting responses to axon injury, and that therapeutic strategies that boost NP may reduce regeneration.
authors.affiliation: Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Derek M
authors.identifier: http://orcid.org/0000-0003-0539-075X
authors.initials: DM
authors.lastname: Nye
authors.affiliation: Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Stone
authors.affiliation: Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Alexis T
authors.initials: AT
authors.lastname: Weiner
authors.affiliation: Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Gheres
authors.affiliation: Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Collins
authors.affiliation: Huck Institutes of the Life Sciences, and Biochemistry and Molecular Biology,The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Melissa M
authors.identifier: http://orcid.org/0000-0002-5021-4360
authors.initials: MM
authors.lastname: Rolls
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000096:biosynthesis / Q000235:genetics; D008870:Microtubules / Q000235:genetics / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D014855:Wallerian Degeneration / Q000235:genetics* / Q000473:pathology
chemical_list: D029721:Drosophila Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; C435749:kay protein, Drosophila; D048670:MAP Kinase Kinase 4; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D020169:Caspases