title: Synapse maturation by activity-dependent ectodomain shedding of SIRPα.
abstract: Formation of appropriate synaptic connections is critical for proper functioning of the brain. After initial synaptic differentiation, active synapses are stabilized by neural activity-dependent signals to establish functional synaptic connections. However, the molecular mechanisms underlying activity-dependent synapse maturation remain to be elucidated. Here we show that activity-dependent ectodomain shedding of signal regulatory protein-α (SIRPα) mediates presynaptic maturation. Two target-derived molecules, fibroblast growth factor 22 and SIRPα, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRPα drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRPα, and the shed ectodomain in turn promotes the maturation of the presynaptic terminal. This process involves calcium/calmodulin-dependent protein kinase, matrix metalloproteinases and the presynaptic receptor CD47. Finally, SIRPα-dependent synapse maturation has an impact on synaptic function and plasticity. Thus, ectodomain shedding of SIRPα is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses.
authors.affiliation: 1] Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA. [2].
authors.forename: Anna B
authors.initials: AB
authors.lastname: Toth
authors.forename: Akiko
authors.initials: A
authors.lastname: Terauchi
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Zhang
authors.forename: Erin M
authors.initials: EM
authors.lastname: Johnson-Venkatesh
authors.forename: David J
authors.initials: DJ
authors.lastname: Larsen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sutton
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D017434:Protein Structure, Tertiary / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure*
chemical_list: C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic
references.citation: J Neurochem. 2008 Jul;106(2):682-95
references.pmid: 18410519
references.citation: Science. 2000 Jun 16;288(5473):2051-4
references.pmid: 10856220
references.citation: Cold Spring Harb Perspect Biol. 2010 Apr;2(4):a001842
references.pmid: 20452946
references.citation: Nat Rev Immunol. 2006 Jun;6(6):457-64
references.pmid: 16691243
references.citation: J Neurosci. 2002 Apr 1;22(7):2835-42
references.pmid: 11923448
references.citation: J Neurochem. 2006 Jun;97(5):1215-31
references.pmid: 16638017
references.citation: Bioessays. 2011 Jan;33(1):61-72
references.pmid: 21110347
references.citation: J Cell Sci. 2006 Jan 1;119(Pt 1):172-83
references.pmid: 16371655
references.citation: Nat Neurosci. 2011 Jun;14(6):688-90
references.pmid: 21532580
references.citation: Nature. 2010 Jun 10;465(7299):783-7
references.pmid: 20505669
references.citation: Curr Opin Neurobiol. 2009 Apr;19(2):154-61
references.pmid: 19481442
references.citation: PLoS One. 2009;4(4):e5251
references.pmid: 19370153
references.citation: Neuron. 2008 Sep 25;59(6):914-31
references.pmid: 18817731
references.citation: J Neurosci Res. 2007 Oct;85(13):2813-23
references.pmid: 17387691
references.citation: Front Mol Neurosci. 2009 Jul 30;2:8
references.pmid: 19668708
references.citation: Nat Protoc. 2007;2(3):670-6
references.pmid: 17406629
references.citation: Genesis. 2002 Jan;32(1):8-18
references.pmid: 11835669
references.citation: Histochemistry. 1993 Dec;100(6):431-40
references.pmid: 7512949
references.citation: Neuron. 2010 Apr 29;66(2):191-7
references.pmid: 20434996
references.citation: Mol Aspects Med. 2008 Oct;29(5):258-89
references.pmid: 18762209
references.citation: Curr Opin Neurobiol. 2011 Feb;21(1):132-43
references.pmid: 20832286
references.citation: Nat Neurosci. 2001 Nov;4 Suppl:1207-14
references.pmid: 11687831
references.citation: J Comp Neurol. 1991 Dec 15;314(3):545-57
references.pmid: 1814974
references.citation: Nat Rev Neurosci. 2007 Mar;8(3):206-20
references.pmid: 17299456
references.citation: Semin Cell Dev Biol. 2009 Apr;20(2):126-37
references.pmid: 19049889
references.citation: J Neurosci. 1989 Jun;9(6):2170-81
references.pmid: 2470877
references.citation: Neuron. 2010 Oct 6;68(1):9-18
references.pmid: 20920787
references.citation: Mol Cell. 2008 Jul 25;31(2):266-77
references.pmid: 18657508
references.citation: Neuron. 2012 Oct 18;76(2):410-22
references.pmid: 23083742
references.citation: J Biol Chem. 2004 Jul 2;279(27):27878-87
references.pmid: 15123722
references.citation: Neuron. 2011 Jun 23;70(6):1128-42
references.pmid: 21689599
references.citation: J Immunol. 2005 Dec 15;175(12):7781-7
references.pmid: 16339510
references.citation: Cell. 2004 Jul 23;118(2):257-70
references.pmid: 15260994
references.citation: Hippocampus. 2006;16(12):1032-60
references.pmid: 17094147
references.citation: Annu Rev Neurosci. 1999;22:389-442
references.pmid: 10202544
references.citation: Annu Rev Neurosci. 2008;31:563-90
references.pmid: 18558867
references.citation: Science. 1996 Nov 1;274(5288):795-8
references.pmid: 8864123
references.citation: Learn Mem. 1999 Sep-Oct;6(5):448-57
references.pmid: 10541465
references.citation: J Neurosci. 2010 Aug 4;30(31):10472-83
references.pmid: 20685990
references.citation: Neuron. 2012 Oct 18;76(2):396-409
references.pmid: 23083741
references.citation: Trends Neurosci. 2010 Mar;33(3):121-9
references.pmid: 20138375
references.citation: Development. 2007 Jun;134(11):2171-81
references.pmid: 17507417
references.citation: Neuron. 2003 Oct 9;40(2):243-64
references.pmid: 14556707
references.citation: Neuron. 2011 Oct 6;72(1):9-21
references.pmid: 21982365
references.citation: J Biol Chem. 2008 Dec 5;283(49):34053-61
references.pmid: 18819922
references.citation: J Biol Chem. 2009 Sep 25;284(39):26613-9
references.pmid: 19628875
references.citation: Annu Rev Neurosci. 2005;28:251-74
references.pmid: 16022596
references.citation: Trends Cell Biol. 2009 Feb;19(2):72-80
references.pmid: 19144521