Molecular Mechanisms Regulating Axon Guidance Receptor Activity
Principal Investigator: William G Wadsworth
Abstract: As the nervous system develops, axons are guided along specific pathways to find their targets and make functional connections. The precise pattern of connections is essential for proper nervous system function. Axon migrations are directed by guidance cues in the extracellular environment. On the surface of migrating axons, receptors detect the cues and produce signals that control cytoskeletal dynamics to direct where an axon extends. Several classes of guidance cues and receptors have been identified, including the UNC-6/netrin cue and the UNC-40/DCC receptor. The molecular mechanisms that determine the directional response when a receptor is ligated by a guidance cue are not well understood. To explore the molecular basis of axon responses, we preformed a genetic screen in C. elegans for mutations that suppress axon guidance defects caused by a specific unc-6 missense allele, rh46. Our results indicate that we uncovered mutations that enhance UNC-40 signaling when UNC-40 is ligated by UNC-6. One mutation is a loss-of-function allele of clec-38, which encodes a protein with a transmembrane and extracellular C-type lectin-like domains. Our preliminary results indicate that clec-38 negatively regulates UNC-40 signaling in several different neurons. In one case, loss of clec- 38 function causes the failure of a neuron cell body to migrate and the precocious UNC-6-dependent formation of its axon. We also uncovered a missense mutation within the unc-40 ectodomain sequence that in combination with unc-6(rh46) causes new axons migration patterns. This response is suppressed when unc- 6(rh46) is replaced with unc-6(rh46ur282) or unc-6(rh46ur301), alleles that have second site mutations that suppress the original rh46 mutation. These intragenic mutations were also recovered from the screen. These observations indicate an interaction between UNC-6 and the UNC-40 ectodomain in vivo and they suggest that the ligated confirmation of the receptor influences the nature of the axon response. We propose to further study the molecular mechanisms through which the UNC-40 signals are regulated. We plan to further characterize CLEC-38, determine other components that regulate UNC- 40 signaling, genetically dissect the signaling which controls the UNC-40 axon response, and extend our genetic screening. PUBLIC HEALTH RELEVANCE: Neurons must make the proper connections in order for a nervous system to function. Understanding the molecular mechanisms that enable molecules to direct neurons to their targets could provide new insights into disorders that affect the wiring of the nervous system and could also prove useful for developing therapeutic agents to treat nerves damaged by injuries or disease.
Funding Period: 2009-03-01 - 2013-06-30
more information: NIH RePORT
- The roles of multiple UNC-40 (DCC) receptor-mediated signals in determining neuronal asymmetry induced by the UNC-6 (netrin) ligandZhennan Xu
Department of Pathology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 5636, USA
Genetics 183:941-9. 2009..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...
- Extracellular matrix regulates UNC-6 (netrin) axon guidance by controlling the direction of intracellular UNC-40 (DCC) outgrowth activityYong Yang
Department of Pathology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America
PLoS ONE 9:e97258. 2014..Together, these results suggest that an extracellular matrix can regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will be oriented in a specific direction. ..
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