NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis.
In this report we examine the biological and molecular basis of the control of sympathetic neuron differentiation and survival by NGF and neurotrophin-3 (NT-3). NT-3 is as efficient as NGF in mediating neuritogenesis and expression of growth-associated genes in NGF-dependent sympathetic neurons, but it is 20-40-fold less efficient in supporting their survival. Both NT-3 and NGF induce similar sustained, long-term activation of TrkA, while NGF is 10-fold more efficient than NT-3 in mediating acute, short-term TrkA activity. At similar acute levels of TrkA activation, NT-3 still mediates neuronal survival two- to threefold less well than NGF. However, a mutant NT-3 that activates TrkC, but not TrkA, is unable to support sympathetic neuron survival or neuritogenesis, indicating that NT-3-mediated TrkA activation is necessary for both of these responses. On the basis of these data, we suggest that NGF and NT-3 differentially regulate the TrkA receptor both with regard to activation time course and downstream targets, leading to selective regulation of neuritogenesis and survival. Such differential responsiveness to two ligands acting through the same Trk receptor has important implications for neurotrophin function throughout the nervous system.
Belliveau
D J
DJ
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Canada.
Krivko
I
I
Kohn
J
J
Lachance
C
C
Pozniak
C
C
Rusakov
D
D
Kaplan
D
D
Miller
F D
FD
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000648:ultrastructure; D020933:Neurotrophin 3; D016716:PC12 Cells; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D020917:Receptor, trkA; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000166:cytology* / Q000187:drug effects
D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC