Neurotrophin-4 Is More Potent than Brain-Derived Neurotrophic Factor in Promoting, Attracting and Suppressing Geniculate Ganglion Neurite Outgrowth

Abstract

The geniculate ganglion, which provides innervation to taste buds in the anterior tongue and palate, is unique among sensory ganglia in that its neurons depend on both neurotrophin-4 (NT4) and brain-derived neurotrophic factor (BDNF) for survival. Whereas BDNF is additionally implicated in taste axon guidance at targeting stages, much less is known about the guidance role of NT4 during targeting, or about either neurotrophin during initial pathfinding. NT4 and BDNF have distinct expression patterns in vivo, raising the possibility of distinct roles. We characterized the influence of NT4 and BDNF on geniculate neurites in collagen I gels at early embryonic through postnatal stages. During early pathfinding to the tongue (embryonic days 12–13; E12–13), NT4 and BDNF promote significantly longer outgrowth than during intralingual targeting (E15–18). NT4 is more potent than BDNF at stimulating neurite outgrowth and both factors exhibit concentration optima, i.e. intermediate concentrations (0.25 ng/ml NT4 or 25 ng/ml BDNF) promote maximal neurite extension and high concentrations (10 ng/ml NT4 or 200 ng/ml BDNF) suppress it. Only partial suppression was seen at E12 (when axons first emerge from the ganglion in vivo) and postnatally, but nearly complete suppression occurred from E13 to E18. We show that cell death is not responsible for suppression. Although blocking the p75 receptor reduces outgrowth at the optimum concentrations of NT4 and BDNF, it did not reduce suppression of outgrowth. We also report that NT4, like BDNF, can act as a chemoattractant for geniculate neurites, and that the tropic influence is strongest during intralingual targeting (E15–18). NT4 does not appear to act as an attractant in vivo, but it may prevent premature invasion of the epithelium by suppressing axon growth.

Decreased plasma neurotrophin-4/5 levels in bipolar disorder patients in mania

“…11 In this line, and given the consistent finding of decreased circulating BDNF levels in BD patients during acute mood episodes, 3,4 decreased plasma levels of NT-4/5 in BD patients in mania were to be expected.…”

Ephrin-B/EphB Signaling Is Required for Normal Innervation of Lingual Gustatory Papillae

“…Since ephrin-B1 labeling was detectable in the mesenchyme and ephrin-B2 was present in the lingual epithelium, we conducted stripe assays to determine if ephrin-B1-Fc or ephrin-B2-Fc fusion proteins repelled or stabilized geniculate neurite outgrowth in vitro. To promote outgrowth, we used BDNF and NT4 because both are required for geniculate neuron survival [42] and promote substantial geniculate neurite outgrowth in vitro [11,12]. Neither NGF nor NT3 support outgrowth from geniculate explants [1].…”

“…Although NT4 is not required for targeting, it is more potent than BDNF in promoting neurite outgrowth [11] so we also evaluated the response of NT4-promoted neurite outgrowth to ephrin-B-Fc stripes. We note that NT4, like BDNF, is necessary for the survival of half of the geniculate neurons, and mice null for both BDNF and NT4, or their high affinity receptor TrkB, lose 95% of the geniculate neurons [45,46].…”

The role of neurotrophin receptors in taste development.

“…Furthermore, DRG neurons in p75 -/-mice are hypersensitive to the Sema3A, indicating that p75 is an important modulator of Sema3A activity ( [152]). Lastly, Sema3F, which is also expressing in the tongue, may also be involved in loss of taste innervation in the p75 -/-mice due to its repellent effect of NT-4 dependent neurite outgrowth ( [63], [55]). …”

“…In vitro studies also showed that p75 is involved in geniculate neurite outgrowth ( [55] Hybridoma Bank) and rabbit anti-P2X3 antibody (1:500, Millipore, #AB5895) were used to label taste buds and taste fibers. Secondary anti-rat Alexa 488 (green) and anti-rabbit Alexa 555 (red) antibodies (1:500, Molecular Probes) were used to visualize taste buds and taste fibers respectively.…”