title: Equivalent Activities of Repulsive Axon Guidance Receptors.
abstract: Receptors on the growth cone at the leading edge of elongating axons play critical guidance roles by recognizing cues via their extracellular domains and transducing signals via their intracellular domains, resulting in changes in direction of growth. An important concept to have emerged in the axon guidance field is the importance of repulsion as a major guidance mechanism. Given the number and variety of different repulsive receptors, it is generally thought that there are likely to be qualitative differences in the signals they transduce. However, the nature of these possible differences is unknown. By creating chimeras using the extracellular and intracellular domains of three different Drosophila repulsive receptors, Unc5, Roundabout (Robo), and Derailed (Drl) and expressing them in defined cells within the embryonic nervous system, we examined the responses elicited by their intracellular domains systematically. Surprisingly, we found no qualitative differences in growth cone response or axon growth, suggesting that, despite their highly diverged sequences, each intracellular domain elicits repulsion via a common pathway. In terms of the signaling pathway(s) used by the repulsive receptors, mutations in the guanine nucleotide exchange factor Trio strongly enhance the repulsive activity of all three intracellular domains, suggesting that repulsion by Unc5, Robo, and Drl, and perhaps repulsion in general, involves Trio activity.
  
  
  CONCLUSIONS
  A prevailing concept that has emerged in the axon guidance field is the importance of repulsion as a guidance mechanism for steering axons to their appropriate targets. Given the number and variety of different repulsive receptors, it is generally thought that there are differences in the signals that they transduce. However, this has never been tested directly. We have used the advanced genetics of Drosophila to compare directly the outputs of different repulsive receptors. Surprisingly, we found no qualitative differences in receptor-mediated repulsion, suggesting that, despite their highly diverged domain structure, each receptor couples to a common repulsive pathway. We went on to show that this common pathway involves Trio, a guanine nucleotide exchange factor known to promote cytoskeletal remodeling.
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: Hong
authors.initials: H
authors.lastname: Long
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yoshikawa
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037 jthomas@salk.edu.
authors.forename: John B
authors.initials: JB
authors.lastname: Thomas
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020439:Growth Cones / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000097905:Roundabout Proteins
chemical_list: D029721:Drosophila Proteins; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; C488771:UNC protein, Drosophila; C094492:DRL protein, Drosophila
keywords: Drosophila; Trio; axon guidance; growth cone; receptor; repulsion
references.citation: J Neurosci. 2006 Mar 22;26(12):3192-205
references.pmid: 16554470
references.citation: Science. 2001 Mar 9;291(5510):1976-82
references.pmid: 11239160
references.citation: Science. 2009 May 15;324(5929):944-7
references.pmid: 19325078
references.citation: Annu Rev Neurosci. 2009;32:383-412
references.pmid: 19400716
references.citation: Cell. 2010 Feb 5;140(3):409-20
references.pmid: 20144763
references.citation: Curr Biol. 2010 Mar 23;20(6):567-72
references.pmid: 20206526
references.citation: Cold Spring Harb Perspect Biol. 2010 May;2(5):a001941
references.pmid: 20452961
references.citation: Cold Spring Harb Perspect Biol. 2011 Jun;3(6). pii: a001727. doi: 10.1101/cshperspect.a001727
references.pmid: 21123392
references.citation: Nature. 1999 Dec 2;402(6761):540-4
references.pmid: 10591215
references.citation: Neuron. 2000 Apr;26(1):93-106
references.pmid: 10798395
references.citation: Cell. 2002 Aug 23;110(4):415-27
references.pmid: 12202032
references.citation: Nature. 2003 Apr 10;422(6932):583-8
references.pmid: 12660735
references.citation: Genetics. 2004 Apr;166(4):1775-82
references.pmid: 15126397
references.citation: Neuron. 2000 Apr;26(1):119-31
references.pmid: 10798397
references.citation: Development. 2005 Apr;132(8):1983-94
references.pmid: 15790972
references.citation: Curr Biol. 2005 Aug 9;15(15):1413-9
references.pmid: 16085495
references.citation: Nat Neurosci. 2006 Feb;9(2):188-94
references.pmid: 16429137
references.citation: Science. 1982 Oct 22;218(4570):348-53
references.pmid: 6289436
references.citation: Nature. 1984 Jul 19-25;310(5974):203-7
references.pmid: 6462206
references.citation: Neuron. 2001 Oct 11;32(1):39-51
references.pmid: 11604137
references.citation: Neuron. 2001 Nov 20;32(4):605-17
references.pmid: 11719202
references.citation: Nature. 2002 Mar 28;416(6879):438-42
references.pmid: 11919634
references.citation: Neuron. 1990 Jan;4(1):61-85
references.pmid: 2310575
references.citation: Neuron. 1993 Mar;10(3):409-26
references.pmid: 8461134
references.citation: Development. 1993 Jun;118(2):401-15
references.pmid: 8223268
references.citation: Development. 1995 Jun;121(6):1769-73
references.pmid: 7600992
references.citation: Nature. 1995 Jul 13;376(6536):171-4
references.pmid: 7603568
references.citation: Science. 1996 Oct 11;274(5285):252-5
references.pmid: 8824191
references.citation: Cell. 1996 Oct 18;87(2):197-204
references.pmid: 8861904
references.citation: Development. 1997 Jul;124(13):2515-25
references.pmid: 9216994
references.citation: Cell. 1998 Jan 23;92(2):205-15
references.pmid: 9458045
references.citation: Development. 1998 Oct;125(19):3915-23
references.pmid: 9729499
references.citation: Curr Opin Neurobiol. 1998 Oct;8(5):582-6
references.pmid: 9811618
references.citation: Cell. 1999 Jun 25;97(7):917-26
references.pmid: 10399919
references.citation: Cell. 1999 Jun 25;97(7):927-41
references.pmid: 10399920
references.citation: Development. 2004 Dec;131(24):6093-105
references.pmid: 15537690
references.citation: Nat Neurosci. 2005 Feb;8(2):156-63
references.pmid: 15657595
references.citation: Cell. 2000 Apr 28;101(3):283-94
references.pmid: 10847683
references.citation: Development. 2006 May;133(9):1845-54
references.pmid: 16613832