BDNF and NT4 play interchangeable roles in gustatory development

Abstract

A limited number of growth factors are capable of regulating numerous developmental processes, but how they accomplish this is unclear. The gustatory system is ideal for examining this issue because the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) have different developmental roles although both of them activate the same receptors, TrkB and p75. Here we first investigated whether the different roles of BDNF and NT4 are due to their differences in temporal and spatial expression patterns. Then, we asked whether or not these two neurotrophins exert their unique roles on the gustatory system by regulating different sets of downstream genes. By using BdnfNt4/Nt4 mice, in which the coding region for BDNF is replaced with NT4, we examined whether the different functions of BDNF and NT4 are interchangeable during taste development. Our results demonstrated that NT4 could mediate most of the unique roles of BDNF during taste development. Specifically, caspase-3-mediated cell death, which was increased in the geniculate ganglion in Bdnf−/− mice, was rescued in BdnfNt4/Nt4 mice. In BDNF knockout mutant mice, tongue innervation was disrupted, and gustatory axons failed to reach their targets. However, disrupted innervation was rescued and target innervation is normal when NT4 replaced BDNF. Genome wide expression analyses revealed that BDNF and NT4 mutant mice exhibited different gene expression profiles in gustatory (geniculate) ganglion. Compared to wild type, the expression of differentiation-, apoptosis- and axon guidance-related genes was changed in BDNF mutant mice, which is consistent with their different roles during taste development. However, replacement of BDNF by NT4 rescued these gene expression changes. These findings indicate that the functions of BDNF and NT4 in taste development are interchangeable. Spatial and temporal differences in BDNF and NT4 expression can regulate differential gene expression in vivo and determine their specific roles during development.

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

“…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]. Although this is consistent with the possibility that BDNF and NT4 support distinct populations of neurons, the finding that NT4 can substitute for BDNF [3] suggests that BDNF and NT4 support the same population of geniculate neurons. NT4-promoted outgrowth showed no preference for either stripe on control coverglasses (Fig.…”

“…Most experiments were conducted with BDNF in the medium to promote neurite outgrowth, because BDNF is the predominant neurotrophin expressed in fungiform papilla epithelium at targeting stages [3,4,7,15]. However, because NT4 is over 10-fold more potent than BDNF [11], it may be present at levels that are sufficient to influence outgrowth, but difficult to detect.…”

“…Several groups have identified guidance cues that influence the timing of contact with and penetration of the pre-gustatory epithelium during embryonic development. Diffusible repellents are implicated in controlling the timing of contact with the epithelium [1,2], and diffusible neurotrophins have a prominent role in the final stage of guidance to gustatory papillae and target penetration [3–15]. Given that taste axons are ultimately restricted to taste bud epithelium, yet can reside adjacent to non-taste epithelium, we reasoned that non-diffusible guidance cues may have a role in preventing innervation of non-taste epithelium or otherwise restricting the arbors of taste axons.…”

Neurotrophic Factors and Their Potential Applications in Tissue Regeneration

“…It has overlapping effect as BDNF in taste sensory neuron development (Huang and Krimm 2014). It also has synergistic effect with GDNF in promoting neuron survival in cultured embryonic rat brain slice (Meyer et al 2001).…”

Neurotrophin signaling and visceral hypersensitivity

“…In addition to its ability in affecting neuronal function via retrograde fashion, BDNF and receptor TrkB more likely undergo antergrade transport away from neuronal cell bodies (Tonra et al, 1998; Ng et al, 2007; Ha et al, 2008). NT-4, which is often interchangeable with BDNF in initiating TrkB-mediated signal transduction, also has a role in the periphery in sensitizing peripheral innervation and sensory sensitivity (Krimm et al, 2006; Aven et al, 2014; Huang and Krimm, 2014). …”