This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prenatal exposure to aryl hydrocarbons such as dioxin is associated with neurobehavioral and motor deficits in humans. Interestingly, the aryl hydrocarbon receptor, AHR-1, which mediates many of the toxicological effects of aryl hydrocarbons, has been genetically linked to axon guidance pathways mediated by the axon guidance cue netrin-1. Netrin-1 plays an important role in the developing nervous system, directing axons to targets and mediating survival of developing neurons. Two vertebrate families of netrin-1 receptors, the Deleted in Colorectal Cancer (DCC) and the UNC5 family, mediate axonal guidance and trophic effects through interactions with netrin-1 and each other. Chemoattraction of axons to netrin-1 is mediated by the DCC receptor family, whereas chemorepulsion is mediated by a netrin-1-dependent complex of DCC and UNC5 family members. We hypothesize that aryl hydrocarbon exposure, acting through AHR-1, causes deficits in netrin-1-mediated axon guidance, contributing to neurological deficits associated with such exposure. To address this, we will define the role of AHR-1 in netrin-1 signaling. First, we will evaluate the role of AHR-1 in mediating stereotyped behavioral responses to netrin-1. Cultured hippocampal neurons exhibit distinct responses to netrin-1, depending on the complement of receptors expressed on the cell surface. For example, axons of neurons expressing DCC and UNC5 exhibit chemorepulsive turning and growth cone collapse in the presence of netrin-1. Utilizing assays that measure these responses, we can assess the requirement for AHR-1 in mediating these events. Additionally, we will evaluate the role of AHR-1 in the regulation of netrin-1-mediated signaling events. Given that AHR-1 functions as a transcription factor, we will also assess the role of AHR-1 in regulating the expression levels of netrin-1 receptors, as well as proteins known to be involved in netrin-1 signaling in cultured rat hippocampal neurons. In sum, the proposed experiments will begin to define the role of AHR-1 in netrin-1 signaling, providing important insights into AHR-1-mediated toxicity in the developing nervous system.
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