Understanding the Function of GFL-Ret Signaling in the Development of the Periphe

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DESCRIPTION (provided by applicant): The mechanisms underlying the establishment and normal physiological function of the neural circuits underlying nociception (the transduction of pain) in the trunk are known to require survival- and growth- promoting neurotrophic factors, of which nerve growth factor (NGF) and the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) are critical. NGF and the GFLs support the development of functionally distinct nociceptors in the trunk by signaling through their respective receptor tyrosine kinases, TrkA and Ret. In addition, NGF and the GFLs are also required for the acquisition of the molecular properties that define the functional characteristics of each nociceptive population, as well as the postnatal maintenance of these neurons. It is unknown, however, whether NGF-TrkA and GFL-Ret signaling serve an analogous role in the development of trigeminal nociceptors, which are, in many ways, molecularly and functionally distinct from nociceptors in the trunk. The first objective of the experiments proposed here is to identify the role of p75, a TrkA co-receptor and a novel constituent of the GFL-Ret receptor complex, in the development and physiological function of dorsal root ganglion (DRG) sensory neurons and their peripheral projections. The second objective is to identify to what extent NGF-TrkA and GFL-Ret signaling are required for the survival of trigeminal nociceptors and their innervation of the tooth pulp, an important trigeminal target receiving purely nociceptive innervation. Collectively, given the well-establishe role of NGF and GDNF as mediators of survival and growth during nociceptive circuit development, and the emerging body of evidence suggesting these factors serve as mediators of hyperalgesia and mechanical allodynia, the experiments proposed here are likely to have important implications for the rational design of therapeutic strategies seeking to combat chronic pain.