Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.
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 dendr...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-12-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5173288?pdf=render |
| _version_ | 1819210814995824640 |
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| author | Li Chen Derek M Nye Michelle C Stone Alexis T Weiner Kyle W Gheres Xin Xiong Catherine A Collins Melissa M Rolls |
| author_facet | Li Chen Derek M Nye Michelle C Stone Alexis T Weiner Kyle W Gheres Xin Xiong Catherine A Collins Melissa M Rolls |
| author_sort | Li Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T06:17:10Z |
| format | Article |
| id | doaj.art-7230ad8014b5482a9e6068c522696548 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-23T06:17:10Z |
| publishDate | 2016-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-7230ad8014b5482a9e6068c5226965482022-12-21T17:57:15ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-12-011212e100650310.1371/journal.pgen.1006503Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.Li ChenDerek M NyeMichelle C StoneAlexis T WeinerKyle W GheresXin XiongCatherine A CollinsMelissa M RollsAxon 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.http://europepmc.org/articles/PMC5173288?pdf=render |
| spellingShingle | Li Chen Derek M Nye Michelle C Stone Alexis T Weiner Kyle W Gheres Xin Xiong Catherine A Collins Melissa M Rolls Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration. PLoS Genetics |
| title | Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration. |
| title_full | Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration. |
| title_fullStr | Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration. |
| title_full_unstemmed | Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration. |
| title_short | Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration. |
| title_sort | mitochondria and caspases tune nmnat mediated stabilization to promote axon regeneration |
| url | http://europepmc.org/articles/PMC5173288?pdf=render |
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