Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons.
Signaling by brain-derived neurotrophic factor (BDNF) via the TrkB receptor, or by neurotrophin-3 (NT3) through the TrkC receptor support distinct populations of sensory neurons. The intracellular signaling pathways activated by Trk (tyrosine kinase) receptors, which in vivo promote neuronal survival and target innervation, are not well understood. Using mice with TrkB or TrkC receptors lacking the docking site for Shc adaptors (trkB(shc/shc) and trkC(shc/shc) mice), we show that TrkB and TrkC promote survival of sensory neurons mainly through Shc site-independent pathways, suggesting that these receptors use similar pathways to prevent apoptosis. In contrast, the regulation of target innervation appears different: in trkB(shc/shc) mice neurons lose target innervation, whereas in trkC(shc/shc) mice the surviving TrkC-dependent neurons maintain target innervation and function. Biochemical analysis indicates that phosphorylation at the Shc site positively regulates autophosphorylation of TrkB, but not of TrkC. Our findings show that although TrkB and TrkC signals mediating survival are largely similar, TrkB and TrkC signals required for maintenance of target innervation in vivo are regulated by distinct mechanisms.
Postigo
Antonio
A
European Molecular Biology Laboratory, D-69117 Heidelberg, Germany.
Calella
Anna Maria
AM
Fritzsch
Bernd
B
Knipper
Marlies
M
Katz
David
D
Eilers
Andreas
A
Schimmang
Thomas
T
Lewin
Gary R
GR
Klein
Rüdiger
R
Minichiello
Liliana
L
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003051:Cochlea / Q000294:innervation; D017124:Conserved Sequence; D007758:Ear, Inner / Q000294:innervation*; D051379:Mice; D008817:Mice, Mutant Strains; D009475:Neurons, Afferent / Q000502:physiology*; D020933:Neurotrophin 3 / Q000378:metabolism; D011506:Proteins; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013569:Synapses; D014722:Vestibule, Labyrinth / Q000294:innervation
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020813:Receptor, trkB; D020812:Receptor, trkC