Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase.
Axons of adult Caenorhabditis elegans neurons undergo robust regenerative growth after laser axotomy. Here we show that axotomy of PLM sensory neurons triggers axonal calcium waves whose amplitude correlates with the extent of regeneration. Genetic elevation of Ca(2+) or cAMP accelerates formation of a growth cone from the injured axon. Elevated Ca(2+) or cAMP also facilitates apparent fusion of axonal fragments and promotes branching to postsynaptic targets. Conversely, inhibition of voltage-gated calcium channels or calcium release from internal stores reduces regenerative growth. We identify the fusogen EFF-1 as critical for axon fragment fusion and the basic leucine zipper domain (bZip) protein CREB (cAMP response element-binding protein) as a key effector for branching. The effects of elevated Ca(2+) or cAMP on regrowth require the MAPKKK (mitogen-activated protein kinase kinase kinase) DLK-1. Increased cAMP signaling can partly bypass the requirement for the bZip protein CEBP-1, a downstream factor of the DLK-1 kinase cascade. These findings reveal the relationship between Ca(2+)/cAMP signaling and the DLK-1 MAPK (mitogen-activated protein kinase) cascade in regeneration.
Ghosh-Roy
Anindya
A
Division of Biological Sciences, Section of Neurobiology, University of California San Diego, La Jolla, California 92093, USA.
Wu
Zilu
Z
Goncharov
Alexandr
A
Jin
Yishi
Y
Chisholm
Andrew D
AD
D000818:Animals; D001369:Axons / Q000378:metabolism*; D019771:Axotomy; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020439:Growth Cones / Q000378:metabolism; D007834:Lasers; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; C470734:EFF-1 protein, C elegans; D008562:Membrane Glycoproteins; D000242:Cyclic AMP; C498050:DLK-1 protein, C elegans; D020930:MAP Kinase Kinase Kinases; D002118:Calcium