KEGG   PATHWAY: cel04361
Entry
cel04361                    Pathway                                

Name
Axon regeneration - Caenorhabditis elegans (nematode)
Description
Many mature central nervous system (CNS) neurons in non-mammals, such as C. elegans, Drosophila, and zebrafish, are able to regenerate after injuries. The MAPK cascade, DLK-1/MKK-4/PMK-3/MAK2, is identified as an essential signaling pathway involved in axon regeneration in C. elegans. Calcium influx, which is triggered by axotomy, is implicated in DLK-1 activation. Another MAP kinase pathway, MLK-1/MEK-1/KGB-1, acts in parallel with the DLK-1 pathway to control growth-cone formation after axotomy. SVH-1, a homolog of the mammalian hepatocyte growth factor and its receptor SVH-2 function upstream of the MLK-1 pathway to promote axon regeneration. There are also inhibitors of regeneration, such as lin-12/Notch and efa-6. It is possible that the C. elegans pathways that inhibit regeneration function to stabilize the mature, uninjured nervous system.
Class
Organismal Systems; Development and regeneration
Pathway map
cel04361  Axon regeneration
cel04361

Organism
Caenorhabditis elegans (nematode) [GN:cel]
Gene
CELE_C48A7.1  egl-19; Voltage-dependent L-type calcium channel subunit alpha [KO:K04851]
CELE_F17C8.1  acy-1; Adenylyl CYclase [KO:K08049] [EC:4.6.1.1]
CELE_ZK909.2  kin-1; Protein kinase domain-containing protein [KO:K04345] [EC:2.7.11.11]
CELE_C35D10.9  ced-4; Cell death protein 4 [KO:K20105]
CELE_C48D1.2  ced-3; Cell death protein 3 subunit P17 [KO:K20106]
CELE_C01B7.6  rpm-1; E3 ubiquitin-protein ligase rpm-1 [KO:K10693] [EC:2.3.2.33]
CELE_F07B7.12  F07B7.12; Uncharacterized protein [KO:K10693] [EC:2.3.2.33]
CELE_F33E2.2  dlk-1; Mitogen-activated protein kinase kinase kinase dlk-1 [KO:K04422] [EC:2.7.11.25]
CELE_F42G10.2  mkk-4; MAP kinase kinase mkk-4 [KO:K04430] [EC:2.7.12.2]
CELE_VZC374L.1  sek-6; Protein kinase domain-containing protein [KO:K04430] [EC:2.7.12.2]
CELE_ZC449.3  sek-3; Protein kinase domain-containing protein [KO:K04430] [EC:2.7.12.2]
CELE_F42G8.3  pmk-2; Mitogen-activated protein kinase pmk-2 [KO:K04441] [EC:2.7.11.24]
CELE_B0218.3  pmk-1; Mitogen-activated protein kinase pmk-1 [KO:K04441] [EC:2.7.11.24]
CELE_F42G8.4  pmk-3; Mitogen-activated protein kinase pmk-3 [KO:K04441] [EC:2.7.11.24]
CELE_C44C8.6  mak-2; MAP kinase-activated protein kinase mak-2 [KO:K04443] [EC:2.7.11.1]
CELE_F22A3.1  ets-4; Transcription factor ets-4 [KO:K09442]
CELE_D1005.3  cebp-1; C/EBP (CCAAT/enhancer-binding protein) homolog [KO:K23479]
CELE_T14E8.1  svh-2; Tyrosine-protein kinase receptor svh-2 [KO:K05099] [EC:2.7.10.1]
CELE_Y55D9A.1  efa-6; Exchange factor for Arf-6 [KO:K12494]
CELE_K11D9.1  klp-7; Kinesin-like protein [KO:K10393]
CELE_EEED8.6  ccpp-6; Cytosolic carboxypeptidase 6 [KO:K23439] [EC:3.4.17.24]
CELE_F08B1.1  vhp-1; Tyrosine-protein phosphatase vhp-1 [KO:K04459] [EC:3.1.3.16 3.1.3.48]
CELE_C05B10.1  lip-1; Dual specificity protein phosphatase lip-1 [KO:K04459] [EC:3.1.3.16 3.1.3.48]
CELE_C07G1.1  svh-1; Serine protease svh-1 [KO:K23489]
CELE_K11D12.10  mlk-1; Mitogen-activated protein kinase kinase kinase mlk-1 [KO:K04417] [EC:2.7.11.25]
CELE_K08A8.1  mek-1; Dual specificity mitogen-activated protein kinase kinase mek-1 [KO:K04431] [EC:2.7.12.2]
CELE_B0478.1  jnk-1; Stress-activated protein kinase jnk-1 [KO:K04440] [EC:2.7.11.24]
CELE_T07A9.3  kgb-1; GLH-binding kinase 1 [KO:K04440] [EC:2.7.11.24]
CELE_ZC416.4  kgb-2; Mitogen-activated protein kinase [KO:K04440] [EC:2.7.11.24]
CELE_F29G9.4  fos-1; Transcription factor fos-1 [KO:K09031]
CELE_B0218.1  faah-1; Fatty acid amide hydrolase 1 [KO:K15528] [EC:3.5.1.99]
CELE_Y56A3A.12  faah-4; Monoglyceride lipase faah-4 [KO:K15528] [EC:3.5.1.99]
CELE_Y41C4A.2  faah-6; Amidase domain-containing protein [KO:K15528] [EC:3.5.1.99]
CELE_C26C6.2  goa-1; Guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
CELE_E02C12.5  gpa-3; Guanine nucleotide-binding protein alpha-3 subunit [KO:K04534]
CELE_F38E1.5  gpa-2; Guanine nucleotide-binding protein alpha-2 subunit [KO:K04534]
CELE_M04C7.1  gpa-15; Guanine nucleotide-binding protein alpha-15 subunit [KO:K04534]
CELE_R10H10.5  gpa-7; Guanine nucleotide-binding protein alpha-7 subunit [KO:K04534]
CELE_T19C4.6  gpa-1; Guanine nucleotide-binding protein alpha-1 subunit [KO:K04534]
CELE_M01D7.7  egl-30; Uncharacterized protein [KO:K04634]
CELE_B0348.4  egl-8; Phosphoinositide phospholipase C [KO:K05858] [EC:3.1.4.11]
CELE_B0545.1  tpa-1; Protein kinase C-like 1 [KO:K06068] [EC:2.7.11.13]
CELE_C09B7.1  ser-7; G_PROTEIN_RECEP_F1_2 domain-containing protein [KO:K04163]
CELE_R06A10.2  gsa-1; G protein, Subunit Alpha [KO:K04632]
CELE_F18G5.3  gpa-12; Guanine nucleotide-binding protein alpha-12 subunit [KO:K04346]
CELE_F13E6.6  rhgf-1; RHo Guanine nucleotide exchange Factor [KO:K07532]
CELE_Y51H4A.3  rho-1; Ras-like GTP-binding protein RhoA [KO:K04513]
CELE_K06A1.6  dgk-5; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]
CELE_C09E10.2  dgk-1; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]
CELE_F54G8.2  dgk-3; Probable diacylglycerol kinase 3 [KO:K00901] [EC:2.7.1.107]
CELE_F46H6.2  dgk-2; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]
CELE_F42A9.1  dgk-4; Diacylglycerol kinase [KO:K00901] [EC:2.7.1.107]
CELE_F38A6.3  hif-1; Hypoxia-inducible factor 1 [KO:K08268]
CELE_ZK1290.2  tph-1; BH4_AAA_HYDROXYL_2 domain-containing protein [KO:K00502] [EC:1.14.16.4]
CELE_C05D2.3  basl-1; BAS-Like [KO:K01593] [EC:4.1.1.28 4.1.1.105]
CELE_C05D2.4  bas-1; Biogenic Amine Synthesis related [KO:K01593] [EC:4.1.1.28 4.1.1.105]
CELE_Y55D5A.5  daf-2; Insulin-like receptor subunit beta [KO:K04527] [EC:2.7.10.1]
CELE_B0334.8  age-1; Phosphatidylinositol 3-kinase age-1 [KO:K00922] [EC:2.7.1.153]
CELE_B0261.2  let-363; Target of rapamycin homolog [KO:K07203] [EC:2.7.11.1]
CELE_T07A9.6  daf-18; Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase daf-18 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
CELE_R13H8.1  daf-16; Forkhead box protein O [KO:K09408]
CELE_F57C7.3  sdn-1; Syndecan [KO:K16336]
CELE_DY3.7  sup-17; Disintegrin and metalloproteinase domain-containing protein 10 homolog [KO:K06704] [EC:3.4.24.81]
CELE_R107.8  lin-12; Protein lin-12 [KO:K02599]
CELE_F35H12.3  sel-12; Presenilin sel-12 [KO:K04505] [EC:3.4.23.-]
CELE_C18E3.8  hop-1; Presenilin hop-1 [KO:K04505] [EC:3.4.23.-]
CELE_ZK524.1  spe-4; Presenilin spe-4 [KO:K04505] [EC:3.4.23.-]
CELE_R04A9.7  R04A9.7; Uncharacterized protein [KO:K04688] [EC:2.7.11.1]
CELE_Y47D3A.16  rsks-1; Ribosomal protein S6 kinase beta [KO:K04688] [EC:2.7.11.1]
CELE_T01C8.1  aak-2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.11]
CELE_PAR2.3  aak-1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.11]
CELE_F40E10.4  slt-1; Slit homolog 1 protein [KO:K06839]
CELE_M03A1.1  vab-1; Ephrin receptor 1 [KO:K05110] [EC:2.7.10.1]
CELE_ZK377.2  sax-3; Protein sax-3 [KO:K06754]
CELE_F41C6.1  unc-6; Netrin unc-6 [KO:K06843]
CELE_Y50D4C.1  unc-34; WH1 domain-containing protein [KO:K23487]
CELE_F10E9.6  mig-10; Abnormal cell migration protein 10 [KO:K23488]
CELE_ZK470.5  nck-1; NCK (Non-Catalytic region of tyrosine Kinase) adaptor protein family [KO:K19862]
CELE_C09G12.8  ced-10; Ras-related protein ced-10 [KO:K04392]
CELE_C35C5.4  mig-2; Uncharacterized protein [KO:K04392]
CELE_K03D3.10  rac-2; Ras-related protein rac-2 [KO:K04392]
CELE_C05G5.6  let-7; microRNA let-7,b [KO:K16980]
CELE_C12C8.3  lin-41; Protein lin-41 [KO:K12035] [EC:2.3.2.27]
CELE_T07D3.7  alg-2; Protein argonaute [KO:K11593]
CELE_R09A1.1  ergo-1; Piwi-like protein ergo-1 [KO:K11593]
CELE_F48F7.1  alg-1; Protein argonaute [KO:K11593]
CELE_W03C9.4  lin-29; Uncharacterized protein [KO:K23480]
Compound
C00076  Calcium cation
C00078  L-Tryptophan
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C00643  5-Hydroxy-L-tryptophan
C00780  Serotonin
C11695  Anandamide
Reference
  Authors
Hisamoto N, Matsumoto K
  Title
Signal transduction cascades in axon regeneration: insights from C. elegans.
  Journal
Curr Opin Genet Dev 44:54-60 (2017)
DOI:10.1016/j.gde.2017.01.010
Reference
  Authors
Chen L, Chisholm AD
  Title
Axon regeneration mechanisms: insights from C. elegans.
  Journal
Trends Cell Biol 21:577-84 (2011)
DOI:10.1016/j.tcb.2011.08.003
Reference
  Authors
Saijilafu, Zhang BY, Zhou FQ
  Title
Signaling pathways that regulate axon regeneration.
  Journal
Neurosci Bull 29:411-20 (2013)
DOI:10.1007/s12264-013-1357-4
Reference
  Authors
El Bejjani R, Hammarlund M
  Title
Neural regeneration in Caenorhabditis elegans.
  Journal
Annu Rev Genet 46:499-513 (2012)
DOI:10.1146/annurev-genet-110711-155550
Reference
  Authors
Chisholm AD
  Title
Cytoskeletal dynamics in Caenorhabditis elegans axon regeneration.
  Journal
Annu Rev Cell Dev Biol 29:271-97 (2013)
DOI:10.1146/annurev-cellbio-101512-122311
Reference
  Authors
Hammarlund M, Jin Y
  Title
Axon regeneration in C. elegans.
  Journal
Curr Opin Neurobiol 27:199-207 (2014)
DOI:10.1016/j.conb.2014.04.001
Reference
  Authors
Pastuhov SI, Hisamoto N, Matsumoto K
  Title
MAP kinase cascades regulating axon regeneration in C. elegans.
  Journal
Proc Jpn Acad Ser B Phys Biol Sci 91:63-75 (2015)
DOI:10.2183/pjab.91.63
Reference
  Authors
Li C, Hisamoto N, Matsumoto K
  Title
Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways.
  Journal
PLoS Genet 11:e1005603 (2015)
DOI:10.1371/journal.pgen.1005603
Reference
  Authors
Chen L, Chuang M, Koorman T, Boxem M, Jin Y, Chisholm AD
  Title
Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase.
  Journal
Elife 4:e08695 (2015)
DOI:10.7554/eLife.08695
Reference
  Authors
Pastuhov SI, Fujiki K, Nix P, Kanao S, Bastiani M, Matsumoto K, Hisamoto N
  Title
Endocannabinoid-Goalpha signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqalpha-PKC-JNK signalling.
  Journal
Nat Commun 3:1136 (2012)
DOI:10.1038/ncomms2136
Reference
  Authors
Belin S, Norsworthy M, He Z
  Title
Independent control of aging and axon regeneration.
  Journal
Cell Metab 19:354-6 (2014)
DOI:10.1016/j.cmet.2014.02.014
Reference
  Authors
Byrne AB, Walradt T, Gardner KE, Hubbert A, Reinke V, Hammarlund M
  Title
Insulin/IGF1 signaling inhibits age-dependent axon regeneration.
  Journal
Neuron 81:561-73 (2014)
DOI:10.1016/j.neuron.2013.11.019
Reference
  Authors
Po MD, Calarco JA, Zhen M
  Title
Releasing the inner inhibition for axon regeneration.
  Journal
Neuron 73:207-9 (2012)
DOI:10.1016/j.neuron.2012.01.002
Reference
  Authors
El Bejjani R, Hammarlund M
  Title
Notch signaling inhibits axon regeneration.
  Journal
Neuron 73:268-78 (2012)
DOI:10.1016/j.neuron.2011.11.017
Reference
  Authors
Gabel CV, Antoine F, Chuang CF, Samuel AD, Chang C
  Title
Distinct cellular and molecular mechanisms mediate initial axon development and adult-stage axon regeneration in C. elegans.
  Journal
Development 135:1129-36 (2008)
DOI:10.1242/dev.013995
Reference
  Authors
Hubert T, Wu Z, Chisholm AD, Jin Y
  Title
S6 kinase inhibits intrinsic axon regeneration capacity via AMP kinase in Caenorhabditis elegans.
  Journal
J Neurosci 34:758-63 (2014)
DOI:10.1523/JNEUROSCI.2886-13.2014
Reference
  Authors
Zou Y, Chiu H, Zinovyeva A, Ambros V, Chuang CF, Chang C
  Title
Developmental decline in neuronal regeneration by the progressive change of two intrinsic timers.
  Journal
Science 340:372-376 (2013)
DOI:10.1126/science.1231321
Reference
  Authors
Nix P, Bastiani M
  Title
Neuroscience. Heterochronic genes turn back the clock in old neurons.
  Journal
Science 340:282-3 (2013)
DOI:10.1126/science.1237921
Related
pathway
cel04150  mTOR signaling pathway
KO pathway
ko04361   
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