Drosophila neurexin IV interacts with Roundabout and is required for repulsive midline axon guidance.
Slit/Roundabout (Robo) signaling controls midline repulsive axon guidance. However, proteins that interact with Slit/Robo at the cell surface remain largely uncharacterized. Here, we report that the Drosophila transmembrane septate junction-specific protein Neurexin IV (Nrx IV) functions in midline repulsive axon guidance. Nrx IV is expressed in the neurons of the developing ventral nerve cord, and nrx IV mutants show crossing and circling of ipsilateral axons and fused commissures. Interestingly, the axon guidance defects observed in nrx IV mutants seem independent of its other binding partners, such as Contactin and Neuroglian and the midline glia protein Wrapper, which interacts in trans with Nrx IV. nrx IV mutants show diffuse Robo localization, and dose-dependent genetic interactions between nrx IV/robo and nrx IV/slit indicate that they function in a common pathway. In vivo biochemical studies reveal that Nrx IV associates with Robo, Slit, and Syndecan, and interactions between Robo and Slit, or Nrx IV and Slit, are affected in nrx IV and robo mutants, respectively. Coexpression of Nrx IV and Robo in mammalian cells confirms that these proteins retain the ability to interact in a heterologous system. Furthermore, we demonstrate that the extracellular region of Nrx IV is sufficient to rescue Robo localization and axon guidance phenotypes in nrx IV mutants. Together, our studies establish that Nrx IV is essential for proper Robo localization and identify Nrx IV as a novel interacting partner of the Slit/Robo signaling pathway.
Banerjee
Swati
S
Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7545, USA.
Blauth
Kevin
K
Peters
Kimberly
K
Rogers
Stephen L
SL
Fanning
Alan S
AS
Bhat
Manzoor A
MA
D000818:Animals; D001369:Axons / Q000502:physiology*; D016466:CHO Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000097905:Roundabout Proteins
D015816:Cell Adhesion Molecules, Neuronal; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; C491321:Nrx protein, Drosophila; C066819:sli protein, Drosophila
Cell. 2000 Dec 22;103(7):1019-32
11163179
Cell. 1999 Mar 19;96(6):795-806
10102268
Development. 1995 Jun;121(6):1769-73
7600992
Cell. 1991 Feb 22;64(4):801-15
1997208
Cell. 2001 Oct 19;107(2):209-21
11672528
Nat Neurosci. 2005 Feb;8(2):156-63
15657595
Crit Rev Biochem Mol Biol. 2004 Sep-Dec;39(5-6):319-41
15763708
Neuron. 1993 Mar;10(3):409-26
8461134
Nat Biotechnol. 2001 Feb;19(2):153-6
11175730
Neuron. 1996 Aug;17(2):217-28
8780646
Nat Protoc. 2008;3(4):606-11
18388942
Dev Biol. 2002 Dec 1;252(1):46-58
12453459
Cell. 2000 Dec 22;103(7):1033-45
11163180
Development. 2007 Nov;134(21):3795-804
17933790
Development. 2000 May;127(9):1991-2000
10751187
J Neurosci. 2006 Mar 22;26(12):3319-29
16554482
Development. 2004 Oct;131(20):4931-42
15459097
Dev Biol. 2008 May 15;317(2):585-99
18407259
Neuron. 1996 Aug;17(2):203-15
8780645
Development. 1999 Jun;126(11):2475-81
10226006
Annu Rev Neurosci. 2009;32:383-412
19400716
Cell. 1996 Oct 18;87(2):197-204
8861904
Development. 2009 Apr;136(8):1251-61
19261699
Genes Dev. 1990 Dec;4(12A):2169-87
2176636
Neuron. 2003 Sep 25;40(1):113-27
14527437
Cell. 2000 Jun 23;101(7):703-15
10892742
J Cell Biol. 2008 Jul 28;182(2):241-8
18663139
Development. 2009 Apr;136(7):1147-57
19270173
Neuron. 1998 Nov;21(5):991-1001
9856456
Nat Neurosci. 2006 Feb;9(2):188-94
16429137
Curr Biol. 2005 Dec 20;15(24):2271-8
16360689
Neuron. 2001 Nov 20;32(4):605-17
11719202
Dev Cell. 2008 Nov;15(5):704-13
19000835
Cell. 2010 Feb 5;140(3):409-20
20144763
Cell. 1996 Dec 13;87(6):1059-68
8978610
Cell. 2002 Aug 23;110(4):415-27
12202032
Cell. 1999 Mar 19;96(6):785-94
10102267
Cell. 1998 Jan 23;92(2):205-15
9458045
Science. 1996 Nov 15;274(5290):1123-33
8895455
Prog Neurobiol. 2000 Dec;62(5):475-508
10869780
Neuron. 2006 Nov 22;52(4):595-607
17114045
Curr Biol. 2004 Feb 3;14(3):225-30
14761655
Development. 2008 Dec;135(23):3839-48
18948420
Curr Biol. 2004 Mar 23;14(6):499-504
15043815
J Neurosci. 2007 Mar 28;27(13):3584-92
17392474
Trends Genet. 1995 Aug;11(8):324-5
8585131
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11984-8
19574454
Science. 2009 May 15;324(5929):944-7
19325078
Genetics. 2007 Mar;175(3):1505-31
17194782