| Summary: | A PCR screen, conducted in a previous study, to identify novel candidates involved in regulating the survival and growth of developing neurons, identified transcripts for the tumor necrosis factor receptor (TNFR) superfamily member receptor activator of NF-kB (RANK) in the experimentally tractable sensory neurons of the mouse nodose, trigeminal and superior cervical ganglia. Immunohistochemistry revealed coexpression of RANK, together with its ligand, RANKL, and osteoprotegerin (OPG), a decoy receptor, in all nodose, trigeminal and superior cervical gangia neurons in neonates. Over-expressing RANK inhibited BDNF- and CNTF-promoted neurite growth in nodose neurons, and NGF-promoted neurite growth in SCG and trigeminal neurons, without affecting neuronal survival. This effect was seen across a range of developmental ages, from embryonic timepoints, to postnatal ages, suggesting a fundamental role for this receptor in regulating neurotrophin-mediated neurite growth. Investigations revealed the requirement of TRAF2, NIK, IKKp and NF-kB, but not TRAF6 or IKKa, for RANK-mediated inhibition of BDNF-mediated neuritic outgrowth from nodose neurons at a time when neurons are extending axons and ramifying in their targets. Exploration of other possible RANK signalling mediators revealed a role for the important intracellular kinases, MEK and Akt, in the regulation of BDNF- mediated neuritic outgrowth from early postnatal nodose neurons. Akt was found to positively regulate BDNF-mediated neuritic outgrowth, while MEK negatively regulates the outgrowth mediated by this neurotrophin.
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