title: A Novel, Noncanonical BMP Pathway Modulates Synapse Maturation at the Drosophila Neuromuscular Junction.
abstract: At the Drosophila NMJ, BMP signaling is critical for synapse growth and homeostasis. Signaling by the BMP7 homolog, Gbb, in motor neurons triggers a canonical pathway-which modulates transcription of BMP target genes, and a noncanonical pathway-which connects local BMP/BMP receptor complexes with the cytoskeleton. Here we describe a novel noncanonical BMP pathway characterized by the accumulation of the pathway effector, the phosphorylated Smad (pMad), at synaptic sites. Using genetic epistasis, histology, super resolution microscopy, and electrophysiology approaches we demonstrate that this novel pathway is genetically distinguishable from all other known BMP signaling cascades. This novel pathway does not require Gbb, but depends on presynaptic BMP receptors and specific postsynaptic glutamate receptor subtypes, the type-A receptors. Synaptic pMad is coordinated to BMP's role in the transcriptional control of target genes by shared pathway components, but it has no role in the regulation of NMJ growth. Instead, selective disruption of presynaptic pMad accumulation reduces the postsynaptic levels of type-A receptors, revealing a positive feedback loop which appears to function to stabilize active type-A receptors at synaptic sites. Thus, BMP pathway may monitor synapse activity then function to adjust synapse growth and maturation during development.
authors.affiliation: Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Mikolaj J
authors.initials: MJ
authors.lastname: Sulkowski
authors.affiliation: Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Han
authors.affiliation: Cellular Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ott
authors.affiliation: Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Verheyen
authors.affiliation: Cellular Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lippincott-Schwartz
authors.affiliation: Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Serpe
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D009046:Motor Neurons / Q000378:metabolism; D009469:Neuromuscular Junction / Q000235:genetics* / Q000254:growth & development; D038081:Organogenesis; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D016212:Transforming Growth Factor beta
references.citation: Neuron. 2004 Feb 19;41(4):521-34
references.pmid: 14980202
references.citation: Neuron. 2004 Mar 25;41(6):891-905
references.pmid: 15046722
references.citation: J Neurosci. 2005 Mar 23;25(12):3209-18
references.pmid: 15788778
references.citation: FEBS Lett. 1998 Aug 28;434(1-2):83-7
references.pmid: 9738456
references.citation: Neuron. 2002 Feb 14;33(4):545-58
references.pmid: 11856529
references.citation: J Biol Chem. 2012 Nov 16;287(47):39492-504
references.pmid: 22961979
references.citation: FEBS Lett. 2012 Jul 4;586(14):1871-84
references.pmid: 22617150
references.citation: Neuron. 1996 Oct;17(4):627-40
references.pmid: 8893021
references.citation: J Neurosci. 1997 Jan 15;17(2):755-64
references.pmid: 8987797
references.citation: J Neurosci. 2002 Nov 1;22(21):9399-409
references.pmid: 12417665
references.citation: Birth Defects Res A Clin Mol Teratol. 2012 Oct;94(10):804-16
references.pmid: 22865775
references.citation: Neuron. 2000 May;26(2):313-29
references.pmid: 10839352
references.citation: J Cell Biol. 2003 Sep 15;162(6):1089-98
references.pmid: 12963706
references.citation: Neuron. 2007 Sep 6;55(5):741-55
references.pmid: 17785181
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: Eur J Neurosci. 2004 Oct;20(8):2031-7
references.pmid: 15450082
references.citation: Physiol Rev. 1980 Oct;60(4):1284-335
references.pmid: 6159658
references.citation: J Cell Biol. 2009 May 18;185(4):713-25
references.pmid: 19451277
references.citation: Neuron. 2002 Feb 14;33(4):529-43
references.pmid: 11856528
references.citation: Curr Opin Genet Dev. 1996 Aug;6(4):432-8
references.pmid: 8791534
references.citation: Fly (Austin). 2008 Sep-Oct;2(5):259-61
references.pmid: 20798607
references.citation: Curr Biol. 2014 Sep 8;24(17):2059-65
references.pmid: 25131677
references.citation: Annu Rev Cell Dev Biol. 2005;21:659-93
references.pmid: 16212511
references.citation: Dev Cell. 2008 Jan;14(1):108-19
references.pmid: 18194657
references.citation: Nat Rev Neurosci. 2013 Jan;14(1):7-23
references.pmid: 23254191
references.citation: PLoS Genet. 2012;8(11):e1003031
references.pmid: 23144627
references.citation: Nat Rev Mol Cell Biol. 2007 Dec;8(12):970-82
references.pmid: 18000526
references.citation: Neuron. 2010 May 27;66(4):536-49
references.pmid: 20510858
references.citation: J Neurosci. 2013 Nov 6;33(45):17937-50
references.pmid: 24198381
references.citation: J Neurosci. 2010 Jun 16;30(24):8138-50
references.pmid: 20554864
references.citation: Neuron. 1997 Dec;19(6):1237-48
references.pmid: 9427247
references.citation: Genetics. 1995 Mar;139(3):1347-58
references.pmid: 7768443
references.citation: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1545-64
references.pmid: 16939974
references.citation: Proc Natl Acad Sci U S A. 2015 May 12;112(19):6182-7
references.pmid: 25918369
references.citation: Neuron. 2007 Oct 4;56(1):109-23
references.pmid: 17920019
references.citation: J Cell Sci. 2005 Aug 15;118(Pt 16):3573-84
references.pmid: 16105881
references.citation: J Neurosci. 1999 Apr 15;19(8):3023-32
references.pmid: 10191319
references.citation: Development. 2014 Jan;141(2):436-47
references.pmid: 24353060
references.citation: PLoS Genet. 2015;11(2):e1004988
references.pmid: 25723514
references.citation: Neuron. 2010 Jun 10;66(5):724-38
references.pmid: 20547130
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7643-8
references.pmid: 16672363
references.citation: J Biol Chem. 2011 Jun 3;286(22):19287-96
references.pmid: 21471205
references.citation: Neuron. 2006 Mar 16;49(6):833-44
references.pmid: 16543132
references.citation: Mech Dev. 1999 Aug;86(1-2):171-5
references.pmid: 10446278
references.citation: J Neurosci. 2014 Mar 19;34(12):4371-81
references.pmid: 24647957
references.citation: Cell Signal. 2013 Dec;25(12):2717-26
references.pmid: 24018044
references.citation: PLoS Genet. 2015 Apr;11(4):e1005191
references.pmid: 25905467
references.citation: Nat Neurosci. 2012 Sep;15(9):1219-26
references.pmid: 22864612
references.citation: PLoS One. 2014;9(9):e107443
references.pmid: 25255438
references.citation: Neuron. 2003 Jul 17;39(2):241-54
references.pmid: 12873382
references.citation: Nat Neurosci. 2005 Jul;8(7):898-905
references.pmid: 16136672
references.citation: Neuron. 2006 Jul 6;51(1):57-69
references.pmid: 16815332
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: PLoS One. 2009;4(8):e6543
references.pmid: 19657393
references.citation: Neuron. 2008 May 22;58(4):507-18
references.pmid: 18498733
references.citation: J Cell Biol. 2014 Mar 31;204(7):1157-72
references.pmid: 24662564
references.citation: Cell Res. 2009 Jan;19(1):128-39
references.pmid: 19114990
references.citation: Neuron. 1998 Dec;21(6):1465-75
references.pmid: 9883738
references.citation: Development. 2007 Jun;134(11):2061-71
references.pmid: 17507407
references.citation: Curr Biol. 2006 Mar 21;16(6):591-8
references.pmid: 16546084
references.citation: PLoS Biol. 2008 Nov 18;6(11):e284
references.pmid: 19018662
references.citation: Nature. 2014 Oct 16;514(7522):328-34
references.pmid: 25119039
references.citation: Development. 2006 Dec;133(24):4969-79
references.pmid: 17119021
references.citation: Genes Dev. 2009 Nov 1;23(21):2551-62
references.pmid: 19884260
references.citation: Curr Biol. 2012 Oct 9;22(19):1831-8
references.pmid: 22959350
references.citation: J Physiol. 1994 Dec 1;481 ( Pt 2):371-83
references.pmid: 7537815
references.citation: Annu Rev Cell Biol. 1990;6:597-641
references.pmid: 2177343
references.citation: Nat Methods. 2011 Sep;8(9):737-43
references.pmid: 21985007
references.citation: Neuron. 1998 Feb;20(2):305-15
references.pmid: 9491991
references.citation: J Comp Physiol A. 1994 Aug;175(2):179-91
references.pmid: 8071894
references.citation: Nat Neurosci. 2007 Feb;10(2):177-85
references.pmid: 17220882
references.citation: Neuron. 2005 Sep 1;47(5):695-708
references.pmid: 16129399
references.citation: Int Rev Neurobiol. 2006;75:165-79
references.pmid: 17137928
references.citation: J Neurosci. 2010 Apr 14;30(15):5253-68
references.pmid: 20392948
references.citation: EMBO J. 2004 Dec 8;23(24):4792-801
references.pmid: 15538389
references.citation: Nature. 2008 Oct 16;455(7215):903-11
references.pmid: 18923512
references.citation: Dev Neurobiol. 2012 Dec;72(12):1541-58
references.pmid: 22467519
references.citation: Development. 2006 Jan;133(2):183-93
references.pmid: 16368928
references.citation: Fly (Austin). 2007 Jul-Aug;1(4):212-21
references.pmid: 18820452
references.citation: BMC Struct Biol. 2007;7:6
references.pmid: 17295905
references.citation: Dev Biol. 2010 Jan 15;337(2):375-85
references.pmid: 19914231
references.citation: Mol Cell Neurosci. 2012 Nov;51(3-4):89-100
references.pmid: 22954894
references.citation: Mech Dev. 2000 Jul;95(1-2):201-6
references.pmid: 10906462
references.citation: FEBS Lett. 2012 Jul 4;586(14):1929-41
references.pmid: 22710177
references.citation: J Neurosci. 2004 Feb 11;24(6):1406-15
references.pmid: 14960613
references.citation: BMC Neurosci. 2005;6:44
references.pmid: 15985179
references.citation: Adv Exp Med Biol. 2012;970:3-28
references.pmid: 22351049
references.citation: Genetics. 1995 Jan;139(1):241-54
references.pmid: 7705627
references.citation: Genetics. 2009 Oct;183(2):563-79, 1SI-8SI
references.pmid: 19620392
references.citation: PLoS One. 2013 Jun 19;8(6):e65997
references.pmid: 23840387
references.citation: Nat Neurosci. 2013 Sep;16(9):1248-56
references.pmid: 23892553
references.citation: J Cell Sci. 2012 Aug 15;125(Pt 16):3752-64
references.pmid: 22573823
references.citation: Nature. 2009 Dec 10;462(7274):745-56
references.pmid: 19946266
references.citation: Genetics. 1999 Jun;152(2):629-40
references.pmid: 10353905
references.citation: Int Rev Neurobiol. 2006;75:323-65
references.pmid: 17137935
references.citation: Dev Cell. 2014 Dec 8;31(5):586-98
references.pmid: 25453556
references.citation: Genes Dev. 2012 May 1;26(9):974-87
references.pmid: 22499592
references.citation: Development. 2011 Aug;138(15):3179-88
references.pmid: 21750029
references.citation: Curr Biol. 2006 Apr 4;16(7):625-35
references.pmid: 16581507
references.citation: J Cell Biol. 2009 Jul 13;186(1):129-45
references.pmid: 19596851
references.citation: J Neurosci. 2007 Jul 18;27(29):7740-50
references.pmid: 17634368
references.citation: Annu Rev Neurosci. 2006;29:307-23
references.pmid: 16776588