PLCγ-activated signalling is essential for TrkB mediated sensory neuron structural plasticity

Abstract

BackgroundThe vestibular system provides the primary input of our sense of balance and spatial orientation. Dysfunction of the vestibular system can severely affect a person's quality of life. Therefore, understanding the molecular basis of vestibular neuron survival, maintenance, and innervation of the target sensory epithelia is fundamental.ResultsHere we report that a point mutation at the phospholipase Cγ (PLCγ) docking site in the mouse neurotrophin tyrosine kinase receptor TrkB (Ntrk2) specifically impairs fiber guidance inside the vestibular sensory epithelia, but has limited effects on the survival of vestibular sensory neurons and growth of afferent processes toward the sensory epithelia. We also show that expression of the TRPC3 cation calcium channel, whose activity is known to be required for nerve-growth cone guidance induced by brain-derived neurotrophic factor (BDNF), is altered in these animals. In addition, we find that absence of the PLCγ mediated TrkB signalling interferes with the transformation of bouton type afferent terminals of vestibular dendrites into calyces (the largest synaptic contact of dendrites known in the mammalian nervous system) on type I vestibular hair cells; the latter are normally distributed in these mutants as revealed by an unaltered expression pattern of the potassium channel KCNQ4 in these cells.ConclusionsThese results demonstrate a crucial involvement of the TrkB/PLCγ-mediated intracellular signalling in structural aspects of sensory neuron plasticity.

BDNF and NT4 play interchangeable roles in gustatory development

“…Neuron survival is normally regulated by both neurotrophins, but only BDNF is required for correct targeting and guidance. Targeting may utilize different signaling pathways downstream of the TrkB receptor than those employed in neuron survival (Sciarretta et al, 2010). In fact there is considerable evidence that not only do NT4 and BDNF function by activating different signaling mechanisms, neuron survival and targeting are mediated by differential signaling (Gartner et al, 2006; Ming et al, 2002; Minichiello, 2009; Minichiello et al, 2002; Postigo et al, 2002; Sciarretta et al, 2010).…”

“…These findings demonstrate that the functions of the two factors are largely interchangeable. This was surprising, because these two neurotrophic factors can activate different signaling pathway through the same Trk receptor (Berghuis et al, 2006; Bibel and Barde, 2000; Huang and Reichardt, 2003; Minichiello, 2009; Minichiello et al, 1998; Sciarretta et al, 2010). However, for the developing taste system it is primarily location and timing that dictates the function of the two TrkB ligands.…”

“…Alternatively, neurotrophins can achieve diverse functions by activating different internal signaling pathways downstream of Trk receptor binding. It has been shown that Shc- and phospholipase Cγ1-dependent pathways downstream of TrkB, play distinct roles in neuronal survival, targeting innervation and synaptic plasticity (Gartner et al, 2006; Minichiello et al, 2002; Musumeci et al, 2009; Postigo et al, 2002; Sciarretta et al, 2010). BDNF and NT4 could exert different functions by activating distinct signaling pathways downstream of TrkB.…”

Structure and development of cochlear afferent innervation in mammals

“…These interactions were also found to be essential for survival of SGNs, as it was shown that targeted deletions of either BDNF and NT-3 (26,78) or trkB and trkC receptors (108,149,151,160) result in loss of SGNs. In addition, mice lacking both the phospholipase C␥ (PLC␥) and the Shc binding sites of trkB have recently been described producing a similar cochlear phenotype to that seen in trkB-null mice, supporting the idea that the trkB signaling pathway predominantly depends on these two docking sites (155). Taken together, the analysis of single receptor-or ligand-deficient mice initially suggested that BDNF and NT-3 specifically support the innervation of OHCs and IHCs, respectively (35,39,77).…”

Involvement of phospholipase C-γ in the pro-survival role of glial cell line-derived neurotrophic factor in developing motoneurons in rat spinal cords

“…Previous studies have found that GDNF signals through a unique multicomponent receptor system consisting of RET tyrosine kinase and glycosylphosphatidylinositolanchored co-receptor (GFRα1-4) in the cell membrane (9). Notably, the GDNF-TrkB signaling pathway has been proven to be involved in the transcription, translation and trafficking of proteins during neuronal and synaptic plasticity of the nervous system (10,11), and these functions are carried out by a combination of the three signaling cascades triggered when GDNF binds TrkB: the mitogen-activated protein kinase (MAPK), phosphoinositide phospholipase C-γ (PLCγ) and phosphatidylinositol 3-kinase (PI3K) pathways (10)(11)(12)(13). The brain-derived neurotrophic factor (BDNF)-PLC-γ pathway has been found to widely participate in many neuronal activities such as neurite outgrowth (14,15) and differentiation (10,16).…”