Sensory neurons that detect noxious stimuli (nociceptors) typically adopt complex dendritic structures with highly branched arrays directly beneath the skin. This feature is conserved in the simple organism, C. elegans, in which the PVD nociceptive neuron exhibits an elaborate pattern of dendritic processes that envelops the animal with a net-like array of sensory endings. Time-lapse imaging showed that the discrete topical region occupied by each PVD dendritic branch is defined by a contact-dependent mechanism in which sister dendrites (i.e., dendritic branches from the same neuron) repel each other during outgrowth. This phenomenon, known as "self-avoidance," may be important for optimizing coverage of the sensory field and for mapping each sensory neuron to a discrete receptive domain. Self-avoidance is evolutionarily conserved in mammals but its mechanism is poorly understood. The goal of the proposed study is to test a novel mechanism of self-avoidance in which "sister" dendritic branches of a single neuron utilize a conserved signaling pathway to communicate with each other to prevent overlapping dendritic outgrowth. My work has revealed the surprising finding that the conserved axon guidance cue, UNC-6/Netrin, is required for sister dendrite self-avoidance;genetic disruption of UNC-6/Netrin or of its receptors, UNC-5 and UNC-40/DCC, abrogates contact-dependent repulsion between sister PVD dendritic branches. I propose to test this model and to elucidate the mechanism whereby a diffusible UNC-6/Netrin cue controls self-avoidance with the following experiments: (1) Establish the cell-autonomous roles of UNC-5 and UNC-40/DCC in PVD dendritic branch self-avoidance. (2) Determine the role of UNC-6/Netrin permissive signaling in dendritic self-avoidance. (3) Characterize the mechanism by which MIG-10/Lpd and additional downstream components control actin dynamics of UNC-6/Netrin contact-mediated self-avoidance. Because UNC-6/Netrin and its cytoplasmic signaling components are conserved in mammals, it is reasonable to expect that the results of this work will reveal a fundamental mechanism for patterning nociceptor architecture in humans.
The perception of pain depends on specialized "nociceptive" neurons that display a net-like array of highly branched extensions or sensory dendrites directly beneath the skin. To identify genes that regulate the creation of these complex structures, we are studying the development of a model nociceptive neuron in a simple organism, the nematode C. elegans. The results of the work should reveal genes with similar roles in vertebrate dendritic patterning and therefore may provide insights that lead to a deeper understanding of the biological basis for disorders that perturb the functional morphology of human neurons.
|Smith, Cody J; O'Brien, Timothy; Chatzigeorgiou, Marios et al. (2013) Sensory neuron fates are distinguished by a transcriptional switch that regulates dendrite branch stabilization. Neuron 79:266-80|
|Smith, Cody J; Watson, Joseph D; VanHoven, Miri K et al. (2012) Netrin (UNC-6) mediates dendritic self-avoidance. Nat Neurosci 15:731-7|