Complement system in neuronal development and plasticity (Homo sapiens)

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131117125, 125, 12111611115, 12213115, 11, 13135, 11, 132, 5, 92, 5, 9151616141641046, 17610310141086, 17163141010661010161017101714121635, 1212132, 121212121, 2, 132, 12931111, 132, 9, 171212121211, 12122, 1223122, 131221211122, 12, 1313251, 1112MACNecessary stimulationNeuronal Progenitor CellLegendmim-inhibitionNeuronmim-catalysisData node of a proteolytic fragmentData node of a metabolitemim-cleavagemim-stimulationPathwaymim-bindingMetabolitemim-conversionTranslocationGeneProductData node of a gene or its productData node of a pathwayExternal granular Layer17Internal granuleLayer17AntibodiesAstrocytesHippocampal neurogenesisand migrationApoptosisSymmetric divisionSynaptic pruningMicrobePathogenTickoverAntigen processing and presentationProliferationCell migrationCell lysisHTRA2BAK1PRKCIMARK3XIAPPARD6BPRKCZC5AR2B cell activationGAS6SCRIBMERTKFASLGCRB2MFGE87CX3CR1LLGL2VasoconstrictionITGB3MARK2CRB1PARD6ADIABLOCell polarityPROS1PATJDLGAP5DEDDFASMARK1Ca2+CASP7AXLITGAVCYCSPARD6GCASP9TYRO3BAXInflammationMPP5PARD3BIDIFNGCASP8CAP1CASP10APAF1CX3CL1H2OC6PiATP8B2CR1OpsonisationCD55TGFB3ChemotaxisCR111MBPCR2ITGB2FCN3CD46C1RC4BPBCFPCOLEC10C4BPACOLEC12C5C8AC3PLSCR1C7VTNCFDTGFB2PLSCR4SERPING1TGFB1MBL1PC8GC4aMg2+ATP11CCFBbC5AR1CFH5CFBMBL2FCN1C2MASP2ITGAMCSMD1ITGAXC4BC1QBFCN2ATP11ACOLEC11C1QAC3AR111ATP10AC8BATPADPATP8B3C1QCC4AC1SSUSD41CASP3CFI11, 12CLUC9ATP8B1PLSCR3MASP1C3H2OC3H2OCFBaC2aC4bC2bC3aC3bCFBCFDCFBbCFBaCFBbC3bCFPCFPC3biC3aC3bCFBbC3bCFPC3bC5aC5bC5bCSMD1CR1ITGB2CFHCFICD55CD46CR1CFIC3dgC7C8GC8AC6C8BC7C8GC8AC6C8BC5bC9CD5913PhosphatidylserinePhosphoethanolaminePhosphatidylserinePhosphoethanolaminePhosphatidylserine16PhosphatidylserineC1QBC1QAC1QCITGB2ITGAMCYCSAPAF1CYCStBIDHTRA2DIABLOCASP3CX3CL1CytosolCell membraneExtracellular matrixPhagocytosisAntigenInflammationChemotaxisMicrogliaPhagocytosisC5AR2C5AR114ApicalBasolateralEmbryonic NPC proliferationNPCNPCCR2176, 17BasolateralApicalNPCNPCNPCCFPC3fC3cMitochondriaC1QBC1QCC1QBC1QAC1QCC1QBC1QCC1QAC1QA2, 9, 17C3b2, 9, 17NucleusC3bC2bC4bGeneProduct


The complement system can be activated through the classical, alternative or leptin pathway. Antigen-antibody complexes are recognised by C1q, which causes the sequential cleavages of C1r and C1s (classical pathway). Collectins and ficolins bind to MBL-associated serine proteases (lectin pathway). Activation of the alternative pathway involves spontaneous hydrolysis of C3 and subsequent cleavages by factors B, D and I. All cascades converge into a common pathway producing opsonins (C3b) that target cells for phagocytosis. Upon increasing activation, subcomponents C5b-C9 form the membrane attack complex (MAC), which induces cellular lysis. Smaller anaphylatoxins (C3a, C4a and C5a) mediate chemotaxis of immune cells and vasoactivation. Furthermore, complement regulator proteins such as SERPING1, Factor H, CSMD1 and CD59 negatively regulate the cascade. Additionally, C3d/CR2 signaling inhibits adult NPC proliferation (green). Anaphylatoxins and lectin components enhance migration (green). C5a-C5aR1 signaling contributes to NPC polarity and proliferation (blue). Apoptotic signaling, TGFβ, C1q, C3b and CR3 mediate selective synaptic pruning of weak synapses.

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  1. Blom AM; ''The role of complement inhibitors beyond controlling inflammation''; J Intern Med., 2017 PubMed Europe PMC Scholia
  2. Hogenaar JTT, van Bokhoven H; ''Schizophrenia: Complement Cleaning or Killing''; Genes (Basel)., 2021 PubMed Europe PMC Scholia
  3. Papanastasiou M, Koutsogiannaki S, Sarigiannis Y, Geisbrecht BV, Ricklin D, Lambris JD; ''Structural Implications for the Formation and Function of the Complement Effector Protein iC3b''; J Immunol., 2017 PubMed Europe PMC Scholia
  4. Janssen BJ, Christodoulidou A, McCarthy A, Lambris JD, Gros P; ''Structure of C3b reveals conformational changes that underlie complement activity''; Nature, 2006 PubMed Europe PMC Scholia
  5. Mayilyan KR, Weinberger DR, Sim RB; ''The complement system in schizophrenia''; Drug News Perspect., 2008 PubMed Europe PMC Scholia
  6. Fatoba O, Itokazu T, Yamashita T; ''Complement cascade functions during brain development and neurodegeneration''; FEBS J., 2021 PubMed Europe PMC Scholia
  7. JJ Neher, U Neniskyte, GC Brown; ''Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration ''; Frontiers in Pharmacology, 2012 PubMed Europe PMC Scholia
  8. Barel M, Balbo M, Gauffre A, Frade R; ''Binding sites of the Epstein-Barr virus and C3d receptor (CR2, CD21) for its three intracellular ligands, the p53 anti-oncoprotein, the p68 calcium binding protein and the nuclear p120 ribonucleoprotein''; Mol Immunol., 1995 PubMed Europe PMC Scholia
  9. Stephan AH, Barres BA, Stevens B; ''The complement system: an unexpected role in synaptic pruning during development and disease''; Annu Rev Neurosci., 2012 PubMed Europe PMC Scholia
  10. M D’Amelio, V Cavallucci, F Cecconi; ''Neuronal caspase-3 signaling: not only cell death''; Cell Death Differ., 2010 PubMed Europe PMC Scholia
  11. Carpanini SM, Torvell M, Morgan BP; ''Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System''; Front Immunol., 2019 PubMed Europe PMC Scholia
  12. Magdalon J, Mansur F, Teles E Silva AL, de Goes VA, Reiner O, Sertié AL; ''Complement System in Brain Architecture and Neurodevelopmental Disorders''; Front Neurosci., 2020 PubMed Europe PMC Scholia
  13. Woo JJ, Pouget JG, Zai CC, Kennedy JL; ''The complement system in schizophrenia: where are we now and what's next?''; Mol Psychiatry., 2020 PubMed Europe PMC Scholia
  14. Suzuki A, Ohno S.; ''The PAR-aPKC system: lessons in polarity''; J Cell Sci., 2006 PubMed Europe PMC Scholia
  15. ''P4-ATPases: lipid flippases in cell membranes''; , PubMed Europe PMC Scholia
  16. Nonaka S, Nakanish H; ''Microglial clearance of focal apoptotic synapses''; Neuroscience Letters, 2019 PubMed Europe PMC Scholia
  17. Coulthard LG, Hawksworth OA, Woodruff TM; ''Complement: The Emerging Architect of the Developing Brain''; Trends Neurosci., 2018 PubMed Europe PMC Scholia


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118898view21:25, 3 June 2021EweitzOntology Term : 'astrocyte' added !
118897view21:25, 3 June 2021EweitzOntology Term : 'microglial cell' added !
118896view21:25, 3 June 2021EweitzOntology Term : 'neuron' added !
118895view21:24, 3 June 2021EweitzOntology Term : 'neural progenitor cell' added !
118866view10:32, 3 June 2021LKooleRemoved TGFBI. Changed colour of 'synaptic pruning' to grey.
118482view05:54, 28 May 2021EgonwReplaced mim-conversions with Arrow
118481view05:49, 28 May 2021EgonwTwo interactions that are not mim-conversion's.
116347view08:32, 3 May 2021LKooleFixed annotations
116327view13:41, 30 April 2021LKooleOntology Term : 'neurodevelopmental disorder pathway' added !
116326view13:38, 30 April 2021LKooleOntology Term : 'complement system pathway' added !
116325view13:36, 30 April 2021LKooleOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
116314view18:49, 29 April 2021LKooleNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetabolite456216 (ChEBI)
APAF1GeneProduct317 (Entrez Gene)
ATP10AGeneProduct57194 (Entrez Gene)
ATP11AGeneProduct23250 (Entrez Gene)
ATP11CGeneProduct286410 (Entrez Gene)
ATP8B1GeneProduct5205 (Entrez Gene)
ATP8B2GeneProduct57198 (Entrez Gene)
ATP8B3GeneProduct148229 (Entrez Gene)
ATPMetaboliteCHEBI:30616 (ChEBI)
AXLGeneProduct558 (Entrez Gene)
Antigen processing and presentationPathwayQ14876119 (Wikidata)
B cell activationPathwayQ14864989 (Wikidata)
BAK1GeneProduct578 (Entrez Gene)
BAXGeneProduct581 (Entrez Gene)
BIDGeneProduct637 (Entrez Gene)
C1QAGeneProduct712 (Entrez Gene)
C1QBGeneProduct713 (Entrez Gene)
C1QCGeneProduct714 (Entrez Gene)
C1RGeneProduct715 (Entrez Gene)
C1SGeneProduct716 (Entrez Gene)
C2GeneProduct717 (Entrez Gene)
C2aProteinR-HSA-166780 (Reactome)
C2bProteinR-HSA-166781 (Reactome)
C3GeneProduct718 (Entrez Gene)
C3AR1GeneProduct719 (Entrez Gene)
C3aProteinR-HSA-166828 (Reactome)
C3bProteinR-HSA-166832 (Reactome)
C3biComplexR-HSA-166832 (Reactome)
C3cComplexR-HSA-3266497 (Reactome)
C3dgProteinR-HSA-3266505 (Reactome)
C3fProteinR-HSA-976779 (Reactome)
C4AGeneProduct720 (Entrez Gene)
C4BGeneProduct721 (Entrez Gene)
C4BPAGeneProduct722 (Entrez Gene)
C4BPBGeneProduct725 (Entrez Gene)
C4aComplexR-HSA-981725 (Reactome)
C4bComplexR-HSA-981700 (Reactome)
C5GeneProduct727 (Entrez Gene)
C5AR1GeneProduct728 (Entrez Gene)
C5AR2GeneProduct27202 (Entrez Gene)
C5aProteinR-HSA-173677 (Reactome)
C5bComplexR-HSA-173671 (Reactome)
C6GeneProduct729 (Entrez Gene)
C7GeneProduct730 (Entrez Gene)
C8AGeneProduct731 (Entrez Gene)
C8BGeneProduct732 (Entrez Gene)
C8GGeneProduct733 (Entrez Gene)
C9GeneProduct735 (Entrez Gene)
CAP1GeneProduct10487 (Entrez Gene)
CASP10GeneProduct843 (Entrez Gene)
CASP3GeneProduct836 (Entrez Gene)
CASP7GeneProduct840 (Entrez Gene)
CASP8GeneProduct841 (Entrez Gene)
CASP9GeneProduct842 (Entrez Gene)
CD46GeneProduct4179 (Entrez Gene)
  • Membrane Cofactor Protein
  • Type your comment here
CD55GeneProduct1604 (Entrez Gene)
  • DAF
  • Type your comment here
CD59GeneProduct966 (Entrez Gene)
CFBGeneProduct629 (Entrez Gene)
CFBaGeneProduct629 (Entrez Gene)
CFBbGeneProduct629 (Entrez Gene)
CFDGeneProduct1675 (Entrez Gene)
CFHGeneProduct3075 (Entrez Gene)
CFIGeneProduct3426 (Entrez Gene)
CFPGeneProduct5199 (Entrez Gene)
CLUGeneProduct1191 (Entrez Gene)
COLEC10GeneProduct10584 (Entrez Gene)
COLEC11GeneProduct78989 (Entrez Gene)
COLEC12GeneProduct81035 (Entrez Gene)
CR1GeneProduct1378 (Entrez Gene)
CR2GeneProduct1380 (Entrez Gene)
CRB1GeneProduct23418 (Entrez Gene)
CRB2GeneProduct286204 (Entrez Gene)
CSMD1GeneProduct64478 (Entrez Gene)
CX3CL1GeneProduct6376 (Entrez Gene)
CX3CR1GeneProduct1524 (Entrez Gene)
CYCSGeneProduct54205 (Entrez Gene)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Cell lysisPathwayQ1218293 (Wikidata)
Cell migrationPathwayQ189092 (Wikidata)
Cell polarityPathwayQ189100 (Wikidata)
ChemotaxisPathwayQ658145 (Wikidata)
DEDDGeneProduct9191 (Entrez Gene)
DIABLOGeneProduct56616 (Entrez Gene)
DLGAP5GeneProduct9787 (Entrez Gene)
FASGeneProduct355 (Entrez Gene)
FASLGGeneProduct356 (Entrez Gene)
FCN1GeneProduct2219 (Entrez Gene)
FCN2GeneProduct2220 (Entrez Gene)
FCN3GeneProduct8547 (Entrez Gene)
GAS6GeneProduct2621 (Entrez Gene)
H2OMetaboliteCHEBI:15377 (ChEBI)
HTRA2GeneProduct27429 (Entrez Gene)
IFNGGeneProduct3458 (Entrez Gene)
ITGAMGeneProduct3684 (Entrez Gene)
ITGAVGeneProduct3685 (Entrez Gene)
ITGAXGeneProduct3687 (Entrez Gene)
ITGB2GeneProduct3689 (Entrez Gene)
ITGB3GeneProduct3690 (Entrez Gene)
InflammationPathwayQ101991 (Wikidata)
LLGL2GeneProduct3993 (Entrez Gene)
MARK1GeneProduct4139 (Entrez Gene)
MARK2GeneProduct2011 (Entrez Gene)
MARK3GeneProduct4140 (Entrez Gene)
MASP1GeneProduct5648 (Entrez Gene)
MASP2GeneProduct10747 (Entrez Gene)
MBL1PGeneProduct8512 (Entrez Gene)
MBL2GeneProduct4153 (Entrez Gene)
MBPGeneProduct4155 (Entrez Gene)
MERTKGeneProduct10461 (Entrez Gene)
MFGE8GeneProduct4240 (Entrez Gene)
MPP5GeneProduct64398 (Entrez Gene)
Mg2+MetaboliteCHEBI:18420 (ChEBI)
OpsonisationPathwayQ14859847 (Wikidata)
PARD3GeneProduct56288 (Entrez Gene)
PARD6AGeneProduct50855 (Entrez Gene)
PARD6BGeneProduct84612 (Entrez Gene)
PARD6GGeneProduct84552 (Entrez Gene)
PATJGeneProduct10207 (Entrez Gene)
PLSCR1GeneProduct5359 (Entrez Gene)
PLSCR3GeneProduct57048 (Entrez Gene)
PLSCR4GeneProduct57088 (Entrez Gene)
PRKCIGeneProduct5584 (Entrez Gene)
PRKCZGeneProduct5590 (Entrez Gene)
PROS1GeneProduct5627 (Entrez Gene)
PhagocytosisPathwayQ184726 (Wikidata)
PhosphatidylserineMetaboliteCHEBI:18303 (ChEBI)
PhosphoethanolamineMetaboliteCHEBI:17553 (ChEBI)
PiMetaboliteCHEBI:24838 (ChEBI)
ProliferationPathwayQ189101 (Wikidata)
SCRIBGeneProduct23513 (Entrez Gene)
SERPING1GeneProduct710 (Entrez Gene)
SUSD4GeneProduct55061 (Entrez Gene)
TGFB1GeneProduct7040 (Entrez Gene)
TGFB2GeneProduct7042 (Entrez Gene)
TGFB3GeneProduct7043 (Entrez Gene)
TYRO3GeneProduct7301 (Entrez Gene)
VTNGeneProduct7448 (Entrez Gene)
VasoconstrictionPathwayQ1067506 (Wikidata)
XIAPGeneProduct331 (Entrez Gene)
tBIDGeneProduct637 (Entrez Gene)
  • Truncated BID
  • Type your comment here

Annotated Interactions

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