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dc.contributor.authorPinan-Lucarre, Berangere
dc.contributor.authorGabel, Christopher V.
dc.contributor.authorReina, Christopher P.
dc.contributor.authorHulme, S. Elizabeth
dc.contributor.authorShevkoplyas, Sergey S.
dc.contributor.authorSlone, R. Daniel
dc.contributor.authorXue, Jian
dc.contributor.authorQiao, Yujie
dc.contributor.authorWeisberg, Sarah
dc.contributor.authorRoodhouse, Kevin
dc.contributor.authorWhitesides, George M.
dc.contributor.authorSamuel, Aravinthan DT
dc.contributor.authorDriscoll, Monica
dc.date.accessioned2012-04-11T17:21:45Z
dc.date.issued2012
dc.identifier.citationBerangere, Pinan-Lucarre, Christopher V. Gabel, Christopher P. Reina, S. Elizabeth Hulme, Segey S. Shevkoplyas, R. Daniel Slone, Jian Xue, et al. 2012. The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans. PLoS Biology 10(5): e1001331.en_US
dc.identifier.issn1544-9173en_US
dc.identifier.issn1545-7885en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:8538260
dc.description.abstractA critical accomplishment in the rapidly developing field of regenerative medicine will be the ability to foster repair of neurons severed by injury, disease, or microsurgery. In C. elegans, individual visualized axons can be laser-cut in vivo and neuronal responses to damage can be monitored to decipher genetic requirements for regeneration. With an initial interest in how local environments manage cellular debris, we performed femtosecond laser axotomies in genetic backgrounds lacking cell death gene activities. Unexpectedly, we found that the CED-3 caspase, well known as the core apoptotic cell death executioner, acts in early responses to neuronal injury to promote rapid regeneration of dissociated axons. In ced-3 mutants, initial regenerative outgrowth dynamics are impaired and axon repair through reconnection of the two dissociated ends is delayed. The CED-3 activator, CED-4/Apaf-1, similarly promotes regeneration, but the upstream regulators of apoptosis CED-9/Bcl2 and BH3-domain proteins EGL-1 and CED-13 are not essential. Thus, a novel regulatory mechanism must be utilized to activate core apoptotic proteins for neuronal repair. Since calcium plays a conserved modulatory role in regeneration, we hypothesized calcium might play a critical regulatory role in the CED-3/CED-4 repair pathway. We used the calcium reporter cameleon to track in vivo calcium fluxes in the axotomized neuron. We show that when the endoplasmic reticulum calcium-storing chaperone calreticulin, CRT-1, is deleted, both calcium dynamics and initial regenerative outgrowth are impaired. Genetic data suggest that CED-3, CED-4 and CRT-1 act in the same pathway to promote early events in regeneration and that CED-3 might act downstream of CRT-1, but upstream of the conserved DLK-1 kinase implicated in regeneration across species. This study documents reconstructive roles for proteins known to orchestrate apoptotic death and links previously unconnected observations in the vertebrate literature to suggest a similar pathway may be conserved in higher organisms.en_US
dc.description.sponsorshipPhysicsen_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pbio.1001331en_US
dash.licenseOAP
dc.titleThe Core Apoptotic Executioner Proteins CED-3 and CED-4 Promote Initiation of Neuronal Regeneration in Caenorhabditis elegansen_US
dc.typeJournal Articleen_US
dc.description.versionAccepted Manuscripten_US
dc.relation.journalPLoS Biologyen_US
dash.depositing.authorSamuel, Aravinthan DT
dc.date.available2012-04-11T17:21:45Z
dash.hope.year2012en_US
dc.identifier.doi10.1371/journal.pbio.1001331*
dash.authorsorderedfalse
dash.contributor.affiliatedWhitesides, George
dash.contributor.affiliatedSamuel, Aravi
dc.identifier.orcid0000-0001-9451-2442


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