Abstract
BackgroundNeurotrophin-4 (NT-4) and brain derived neurotrophic factor (BDNF) bind to the same receptor, Ntrk2/TrkB, but play distinct roles in the development of the rodent gustatory system. However, the mechanisms underlying these processes are lacking.ResultsHere, we demonstrate, in vivo, that single or combined point mutations in major adaptor protein docking sites on TrkB receptor affect specific aspects of the mouse gustatory development, known to be dependent on BDNF or NT-4. In particular, mice with a mutation in the TrkB-SHC docking site had reduced gustatory neuron survival at both early and later stages of development, when survival is dependent on NT-4 and BDNF, respectively. In addition, lingual innervation and taste bud morphology, both BDNF-dependent functions, were altered in these mutants. In contrast, mutation of the TrkB-PLCγ docking site alone did not affect gustatory neuron survival. Moreover, innervation to the tongue was delayed in these mutants and taste receptor expression was altered.ConclusionsWe have genetically dissected pathways activated downstream of the TrkB receptor that are required for specific aspects of the taste system controlled by the two neurotrophins NT-4 and BDNF. In addition, our results indicate that TrkB also regulate the expression of specific taste receptors by distinct signalling pathways. These results advance our knowledge of the biology of the taste system, one of the fundamental sensory systems crucial for an organism to relate to the environment.
Highlights
Neurotrophin-4 (NT-4) and brain derived neurotrophic factor (BDNF) bind to the same receptor, Ntrk2/Tropomyosin-receptor kinase B (TrkB), but play distinct roles in the development of the rodent gustatory system
In order to dissect the contributions of the Sh2-domain containing protein (SHC) and Phospholipase Cγ (PLCγ) docking sites of TrkB in taste system development, and at the same time to determine which of these sites mediate the effect of BDNF and NT-4 in this system, we have studied mouse lines in which Y515 or Y816 have been mutated either singly or in combination [13,14,15]
The TrkB-SHC docking site is necessary and sufficient to mediate TrkB-dependent geniculate neuron survival Loss of Trkb greatly impairs the development of the gustatory system [8,10]
Summary
Neurotrophin-4 (NT-4) and brain derived neurotrophic factor (BDNF) bind to the same receptor, Ntrk2/TrkB, but play distinct roles in the development of the rodent gustatory system. It is well known that the rodent gustatory system develops under tight control of two neurotrophins, brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), preferentially activating their high affinity receptor TrkB [1,2]. Each of these neurotrophins has been previously shown to regulate the survival of about half of the geniculate ganglion neurons, with additive losses observed in newborn mice lacking both BDNF and NT-4 [3,4]. Phosphorylation of Y515 in the juxtamembrane domain, or Y816 in the carboxyl terminus, leads to the recruitment of the adaptor molecules Sh2-domain containing protein (SHC)/fibroblast growth factor receptor substrate 2 (FRS2) and phospholipase Cγ1 (PLCγ1), respectively, with subsequent downstream activation of their respective signalling pathways [11,12]
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