Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor

Abstract

The Trk family of receptor tyrosine kinases and the p75 receptor (p75NTR) mediate the effects of neurotrophins on neuronal survival, differentiation and synaptic plasticity. The neurotrophin BDNF and its cognate receptor tyrosine kinase, TrkB.FL, are highly expressed in neurons of the central nervous system. At later stages in postnatal development the truncated TrkB splice variants (TrkB.T1, TrkB.T2) become abundant. However, the signalling and function of these truncated receptors remained largely elusive. We show that overexpression of TrkB.T1 in hippocampal neurons induces the formation of dendritic filopodia, which are known precursors of synaptic spines. The induction of filopodia by TrkB.T1 occurs independently of neurotrophin binding and of kinase activity of endogenous TrkB.FL. Coexpression of a p75NTR lacking an intracellular domain inhibits the TrkB.T1-induced effect in a dominant negative manner. Steric hindrance of extracellular p75NTR interactions with a specific antibody, or absence of p75NTR with an intact extracellular domain also inhibit this TrkB.T1-induced effect. We thus propose a novel signalling pathway initiated by neurotrophin-independent extracellular or intramembrane interaction of TrkB.T1 with the p75NTR receptor, which modulates dendritic growth via p75NTR signalling cascades.

Long-Term Adeno-Associated Viral Vector-Mediated Expression of Truncated TrkB in the Adult Rat Facial Nucleus Results in Motor Neuron Degeneration

“…Reduced TrkB.FL signaling in facial motor neurons could also result from sequestration of BDNF, NT-4/5, and NT-3 by TrkB.T1 (Biffo et al, 1995). Although overexpression of TrkB.T1 in cortical and hippocampal neurons can produce effects independent of inhibition of TrkB.FL, including distal dendritic growth and filopodia formation (Yacoubian and Lo, 2000;Hartmann et al, 2004), these effects are distinct from the effects we observe after TrkB.T1 overexpression in motor neurons. Thus, our results suggest that a subset of facial motor neurons remains dependent on TrkB.FL signaling in adulthood for the maintenance of structural characteristics.…”

Neurotrophin receptors: Old friends with new partners

“…NT-3 acting on truncated isoform TrkC.T1 activates Rac1 through association with a scaffold protein, tamalin (Esteban et al, 2006) and promotes neural crest cell proliferation and neuronal differentiation via a signaling pathway that requires the participation of p75 NTR (Hapner et al, 1998). Similarly, BDNF binding-truncated isoform TrkB.T1 regulates formation of dendritic filopodia in hippocampal neurons, via a complex with p75 NTR (Hartmann et al, 2004).…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…Thus, density, complexity and the number of spine synapses is increased by both estrogen and BDNF in hippocampus. It is noteworthy, however, that the exact nature of the changes in morphology may;e distinct: some studies indicate that spine shape or length change whereas other studies report that spine synapses are affected [41,[59][60][61][62][63][64][65][66][67][68][69][70][71]. Such data provide some caution to the assumption that estradiol and BDNF have exactly the same effects.…”