title: Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS.
abstract: Neurotrophin receptors corresponding to vertebrate Trk, p75(NTR) or Sortilin have not been identified in Drosophila, thus it is unknown how neurotrophism may be implemented in insects. Two Drosophila neurotrophins, DNT1 and DNT2, have nervous system functions, but their receptors are unknown. The Toll receptor superfamily has ancient evolutionary origins and a universal function in innate immunity. Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. DNT1 (also known as NT1 and spz2) and DNT2 (also known as NT2 and spz5) interact genetically with Toll-6 and Toll-7, and DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously and are distributed in vivo in domains complementary to or overlapping with those of Toll-6 and Toll-7. We conclude that in fruit flies, Tolls are not only involved in development and immunity but also in neurotrophism, revealing an unforeseen relationship between the neurotrophin and Toll protein families.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: McIlroy
authors.forename: Istvan
authors.initials: I
authors.lastname: Foldi
authors.forename: Jukka
authors.initials: J
authors.lastname: Aurikko
authors.forename: Jill S
authors.initials: JS
authors.lastname: Wentzell
authors.forename: Mei Ann
authors.initials: MA
authors.lastname: Lim
authors.forename: Janine C
authors.initials: JC
authors.lastname: Fenton
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Gay
authors.forename: Alicia
authors.initials: A
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007814:Larva; D008124:Locomotion / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D051216:Toll-Like Receptor 6; D051199:Toll-Like Receptor 7; D049452:Green Fluorescent Proteins
references.citation: J Biol Chem. 2008 Nov 21;283(47):32598-609
references.pmid: 18790733
references.citation: Nat Rev Genet. 2008 Mar;9(3):165-78
references.pmid: 18227810
references.citation: Brain Behav Evol. 2006;68(3):145-56
references.pmid: 16912468
references.citation: J Neurosci. 2000 Oct 15;20(20):7556-63
references.pmid: 11027214
references.citation: Prog Neurobiol. 2000 Dec;62(5):475-508
references.pmid: 10869780
references.citation: EMBO Rep. 2002 Jan;3(1):82-7
references.pmid: 11751574
references.citation: Gene Expr Patterns. 2009 Jun;9(5):371-80
references.pmid: 19602393
references.citation: Science. 1994 Apr 29;264(5159):677-83
references.pmid: 8171319
references.citation: Mech Dev. 1998 Mar;72(1-2):141-8
references.pmid: 9533958
references.citation: Dev Cell. 2002 Feb;2(2):159-70
references.pmid: 11832242
references.citation: PLoS One. 2009;4(5):e5441
references.pmid: 19415123
references.citation: Science. 2007 Jul 6;317(5834):86-94
references.pmid: 17615350
references.citation: Dev Dyn. 2000 May;218(1):94-101
references.pmid: 10822262
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Aug 1;64(Pt 8):707-10
references.pmid: 18678937
references.citation: Glia. 2008 Jan 15;56(2):164-76
references.pmid: 18000865
references.citation: Development. 2003 Apr;130(7):1439-48
references.pmid: 12588858
references.citation: Neuron. 2007 Sep 20;55(6):859-73
references.pmid: 17880891
references.citation: Physiology (Bethesda). 2005 Feb;20:70-8
references.pmid: 15653842
references.citation: Trends Neurosci. 2011 May;34(5):269-81
references.pmid: 21419501
references.citation: PLoS Biol. 2008 Nov 18;6(11):e284
references.pmid: 19018662
references.citation: Nat Rev Neurosci. 2005 Aug;6(8):603-14
references.pmid: 16062169
references.citation: Annu Rev Immunol. 2002;20:197-216
references.pmid: 11861602
references.citation: Trends Neurosci. 2011 Jun;34(6):316-25
references.pmid: 21459462
references.citation: J Biol Chem. 2008 May 23;283(21):14629-35
references.pmid: 18347020
references.citation: J Biol Chem. 2010 Jun 18;285(25):19502-9
references.pmid: 20378549
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2429-34
references.pmid: 19164766
references.citation: C R Acad Sci III. 1993 Oct;316(10):1218-24
references.pmid: 8062131
references.citation: Nat Immunol. 2003 Aug;4(8):794-800
references.pmid: 12872120
references.citation: Cell Death Differ. 2006 May;13(5):852-60
references.pmid: 16397579
references.citation: Curr Biol. 2001 Jun 5;11(11):809-21
references.pmid: 11516642
references.citation: Proteins. 2001 Oct 1;45(1):71-80
references.pmid: 11536362
references.citation: Brain Behav Evol. 2006;68(3):124-32
references.pmid: 16912466
references.citation: Nat Rev Immunol. 2009 Jun;9(6):429-39
references.pmid: 19461673
references.citation: Immunity. 2012 Apr 20;36(4):658-67
references.pmid: 22464169
references.citation: Annu Rev Biochem. 2003;72:609-42
references.pmid: 12676795
references.citation: Development. 2007 Jan;134(1):105-16
references.pmid: 17164416
references.citation: Cell Rep. 2013 Mar 28;3(3):595-606
references.pmid: 23499445
references.citation: Cell. 1996 Sep 20;86(6):973-83
references.pmid: 8808632
references.citation: J Cell Biol. 2006 Oct 23;175(2):209-15
references.pmid: 17060494
references.citation: Gene Expr Patterns. 2002 Dec;2(3-4):311-7
references.pmid: 12617819
references.citation: Glia. 2011 Sep;59(9):1296-303
references.pmid: 21732425
references.citation: J Leukoc Biol. 2004 Jan;75(1):18-26
references.pmid: 12960276
references.citation: Science. 1996 Apr 26;272(5261):542-5
references.pmid: 8614802
references.citation: Brain Res. 2000 Feb 14;855(2):274-81
references.pmid: 10677600
references.citation: Nature. 2003 Nov 6;426(6962):33-8
references.pmid: 14603309
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10520-5
references.pmid: 10973475
references.citation: Annu Rev Biochem. 2007;76:141-65
references.pmid: 17362201
references.citation: Dev Cell. 2001 Nov;1(5):679-90
references.pmid: 11709188
references.citation: Dev Growth Differ. 2010 Dec;52(9):771-83
references.pmid: 21158756
references.citation: J Biol Chem. 2007 May 4;282(18):13522-31
references.pmid: 17324925