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The Journal of Neuroscience, April 2, 2008, 28(14):3595-3603; doi:10.1523/JNEUROSCI.5536-07.2008

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Development/Plasticity/Repair
RPM-1, a Caenorhabditis elegans Protein That Functions in Presynaptic Differentiation, Negatively Regulates Axon Outgrowth by Controlling SAX-3/robo and UNC-5/UNC5 Activity

Haichang Li, ^* Gauri Kulkarni, ^* and William G. Wadsworth

Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854-5636

Correspondence should be addressed to William G. Wadsworth, Department of Pathology, Robert Wood Johnson Medical School, 657 Hoes Lane West, Piscataway, NJ 08854-5635. Email: william.wadsworth{at}umdnj.edu

Changes in axon outgrowth patterns are often associated with synaptogenesis. Members of the conserved Pam/Highwire/RPM-1 protein family have essential functions in presynaptic differentiation. Here, we show that Caenorhabditis elegans RPM-1 negatively regulates axon outgrowth mediated by the guidance receptors SAX-3/robo and UNC-5/UNC5. Loss-of-function rpm-1 mutations cause a failure to terminate axon outgrowth, resulting in an overextension of the longitudinal PLM axon. We observe that PLM overextension in rpm-1 mutants is suppressed by sax-3 and unc-5 loss-of-function mutations. PLM axon overextension is also induced by SAX-3 overexpression, and the length of extension is enhanced by loss of rpm-1 function or suppressed by loss of unc-5 function. We also observe that loss of rpm-1 function in genetic backgrounds sensitized for guidance defects disrupts ventral AVM axon guidance in a SAX-3-dependent manner and enhances dorsal guidance of DA and DB motor axons in an UNC-5-dependent manner. Loss of rpm-1 function alters expression of the green fluorescent protein (GFP)-tagged proteins, SAX-3::GFP and UNC-5::GFP. RPM-1 is known to regulate axon termination through two parallel genetic pathways; one involves the Rab GEF (guanine nucleotide exchange factor) GLO-4, which regulates vesicular trafficking, and another that involves the F-box protein FSN-1, which mediates RPM-1 ubiquitin ligase activity. We show that glo-4 but not fsn-1 mutations affect axon guidance in a manner similar to loss of rpm-1 function. Together, the results suggest that RPM-1 regulates axon outgrowth affecting axon guidance and termination by controlling the trafficking of the UNC-5 and SAX-3 receptors to cell membranes.

Key words: axon guidance; Caenorhabditis elegans; development; genetics; growth cone; guidance; receptor

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Received Sept. 17, 2007; revised Feb. 19, 2008; accepted Feb. 29, 2008.

Correspondence should be addressed to William G. Wadsworth, Department of Pathology, Robert Wood Johnson Medical School, 657 Hoes Lane West, Piscataway, NJ 08854-5635. Email: william.wadsworth{at}umdnj.edu

This article has been cited by other articles:

				S. B. Uthaman, T. A. Godenschwege, and R. K. Murphey A Mechanism Distinct from Highwire for the Drosophila Ubiquitin Conjugase Bendless in Synaptic Growth and Maturation J. Neurosci., August 20, 2008; 28(34): 8615 - 8623. [Abstract] [Full Text] [PDF]

				G. Kulkarni, H. Li, and W. G. Wadsworth CLEC-38, A Transmembrane Protein with C-Type Lectin-Like Domains, Negatively Regulates UNC-40-Mediated Axon Outgrowth and Promotes Presynaptic Development in Caenorhabditis elegans J. Neurosci., April 23, 2008; 28(17): 4541 - 4550. [Abstract] [Full Text] [PDF]

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