The role of neurotrophin receptors in taste development.

Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) are two neurotrophins that play distinct roles in geniculate (taste) neuron survival, taste innervation and taste bud formation. These two neurotrophins activate the same receptors tyrosine kinase B (TrkB) and a pan-neurotrophin receptor (p75). While the roles of these neurotrophins have been well studied, it remains unclear how much BDNF and NT-4 function through TrkB and p75 to regulate taste development in vivo. In chapter 2, I compared taste development in TrkB-/- mice and Bdnf-/-/Ntf4-/- mice to determine if these deficits were similar. If so, this would indicate that the functions of both BDNF and NT-4 can be accounted for by TrkB signaling. I found that TrkB-/- mice and Bdnf-/-/Ntf4-/- mice lose the same number of geniculate neurons by E13.5, indicating that BDNF and NT-4 primarily function through TrkB to regulate geniculate neuron survival. Surprisingly, the few geniculate neurons remaining in TrkB-/- mice are more successful in innervating the tongue and taste buds than those remaining in Bdnf-/-/Ntf4-/- mice. As a result these remaining neurons in the TrkB-/- mice innervate and support the development of a surprising number of taste buds. In addition, these remaining neurons do not express the TrkB receptor, indicating the either BDNF or NT-4 must function through an additional receptor to influence taste innervation and/or targeting. The p75 receptor can function as either a pro-survival or pro-death factor during peripheral nervous system development. However, the role of p75 in taste development is unknown. In chapter 3, I examined neuron survival, taste bud formation and tasteinnervation in the p75-/- and TrkB-/-/p75-/- mice. I found that at E13.5, the age after BDNF and NT-4 dependence is established, p75-/- mice did not lose geniculate neurons compared to the wild type mice. This finding indicates that p75 does not mediate neurotrophin neuronal survival at or before this age. Hybrid TrkB-/-/p75-/- mice had the same number of geniculate neurons as TrkB-/- mice, suggesting that p75 does not induce neuron death in the absence of Trk-signaling like it does for some other systems. By E14.5, there is a loss of geniculate neurons in p75-/- mice which continues until E18.5. Also at this age, the pattern of chorda tympani nerve innervation was disrupted in the p75-/- mice. Specifically, the nerves avoid innervating the mid-region of the tongue. Due to the loss of innervation, the taste bud number was decreased in the p75-/- mice. It is possible