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The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in caenorhabditis elegans
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نویسنده
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pinan-lucarre b. ,gabel c.v. ,reina c.p. ,hulme s.e. ,shevkoplyas s.s. ,slone r.d. ,xue j. ,qiao y. ,weisberg s. ,roodhouse k. ,sun l. ,whitesides g.m. ,samuel a. ,driscoll m.
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منبع
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plos biology - 2012 - دوره : 10 - شماره : 5
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چکیده
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A 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. © 2012 pinan-lucarre et al.
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آدرس
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department of molecular biology and biochemistry,rutgers university,piscataway,nj,united states,institut de biologie de l'ecole normale supé rieure,paris, France, department of physics and center for brain science,harvard university,cambridge,ma,united states,department of physiology and biophysics,boston university school of medicine,boston university photonics center,boston,ma, United States, department of molecular biology and biochemistry,rutgers university,piscataway,nj, United States, department of chemistry and chemical biology,harvard university,cambridge,ma, United States, department of biomedical engineering,tulane university,new orleans,la, United States, department of molecular biology and biochemistry,rutgers university,piscataway,nj, United States, department of molecular biology and biochemistry,rutgers university,piscataway,nj, United States, department of molecular biology and biochemistry,rutgers university,piscataway,nj, United States, department of physics and center for brain science,harvard university,cambridge,ma, United States, department of physiology and biophysics,boston university school of medicine,boston,ma, United States, department of physiology and biophysics,boston university school of medicine,boston,ma, United States, department of chemistry and chemical biology,harvard university,cambridge,ma, United States, department of physics and center for brain science,harvard university,cambridge,ma, United States, department of molecular biology and biochemistry,rutgers university,piscataway,nj, United States
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Authors
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