The roles of multiple UNC-40 (DCC) receptor-mediated signals in determining neuronal asymmetry induced by the UNC-6 (netrin) ligand.
The polarization of post-mitotic neurons is poorly understood. Preexisting spatially asymmetric cues, distributed within the neuron or as extracellular gradients, could be required for neurons to polarize. Alternatively, neurons might have the intrinsic ability to polarize without any preestablished asymmetric cues. In Caenorhabditis elegans, the UNC-40 (DCC) receptor mediates responses to the extracellular UNC-6 (netrin) guidance cue. For the HSN neuron, an UNC-6 ventral-dorsal gradient asymmetrically localizes UNC-40 to the ventral HSN surface. There an axon forms, which is ventrally directed by UNC-6. In the absence of UNC-6, UNC-40 is equally distributed and the HSN axon travels anteriorly in response to other cues. However, we find that a single amino acid change in the UNC-40 ectodomain causes randomly oriented asymmetric UNC-40 localization and a wandering axon phenotype. With UNC-6, there is normal UNC-40 localization and axon migration. A single UNC-6 amino acid substitution enhances the mutant phenotypes, whereas UNC-6 second-site amino acid substitutions suppress the phenotypes. We propose that UNC-40 mediates multiple signals to polarize and orient asymmetry. One signal triggers the intrinsic ability of HSN to polarize and causes randomly oriented asymmetry. Concurrently, another signal biases the orientation of the asymmetry relative to the UNC-6 gradient. The UNC-40 ectodomain mutation activates the polarization signal, whereas different forms of the UNC-6 ligand produce UNC-40 conformational changes that allow or prohibit the orientation signal.
Xu
Zhennan
Z
Department of Pathology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5636, USA.
Li
Haichang
H
Wadsworth
William G
WG
D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism / Q000502:physiology; D001665:Binding Sites / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075385:Netrins; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D000075385:Netrins; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans; D049452:Green Fluorescent Proteins
Curr Biol. 2006 May 9;16(9):845-53
16563765
J Neurosci. 2002 Aug 15;22(16):7080-7
12177204
Nat Cell Biol. 2003 Apr;5(4):267-70
12669070
J Neurosci. 2008 Apr 2;28(14):3595-603
18385318
Curr Opin Cell Biol. 2002 Apr;14(2):196-202
11891119
Trends Neurosci. 2008 Feb;31(2):90-8
18201774
Nat Neurosci. 2007 Feb;10(2):161-8
17237777
Curr Biol. 2008 Jun 3;18(11):808-13
18499456
Nat Rev Immunol. 2006 Sep;6(9):693-8
16917510
Science. 2001 Mar 9;291(5510):1976-82
11239160
Neuron. 1996 Jan;16(1):35-46
8562088
J Neurosci. 2008 Apr 23;28(17):4541-50
18434533
Neuron. 2003 Jan 9;37(1):53-65
12526772
Neuron. 1990 Jan;4(1):61-85
2310575
J Cell Sci. 1974 Jul;15(2):321-46
4859215
Development. 2000 Nov;127(21):4655-68
11023868
Cell. 2002 May 31;109(5):599-610
12062103
Cell. 1996 Oct 18;87(2):187-95
8861903
Cell. 2002 May 31;109(5):611-23
12062104
Dev Cell. 2004 Oct;7(4):571-83
15469845
Curr Biol. 2006 May 9;16(9):854-62
16618541
Annu Rev Neurosci. 2003;26:509-63
12677003
Curr Opin Cell Biol. 2007 Apr;19(2):117-23
17306972
Curr Opin Neurobiol. 2007 Feb;17(1):15-21
17254765
Nat Neurosci. 2006 Apr;9(4):511-8
16520734
Neuron. 1992 Nov;9(5):873-81
1329863
Nat Cell Biol. 2002 Jul;4(7):509-13
12080346