NGF utilizes c-Ret via a novel GFL-independent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons.
During postnatal development, sympathetic neurons lose their dependence upon NGF for survival but continue to require NGF for soma and process growth and for development of a mature neurotransmitter phenotype. Although c-Ret is expressed in sympathetic neurons during this period, its function in these transitional processes is unclear. The level of Ret phosphorylation markedly increased with postnatal age in SCG neurons in vitro and in vivo. Postnatal Ret phosphorylation did not require either GFLs or GFR(alpha) coreceptors. Instead, NGF promoted age-dependent Ret phosphorylation with delayed kinetics both in vitro and in vivo. Functionally, maximal NGF-dependent trophism of mature sympathetic neurons required Ret, but not GFR(alpha) coreceptors. Therefore, NGF promotes phosphorylation of the heterologous RTK Ret resulting in augmented growth, metabolism, and gene expression.
Tsui-Pierchala
Brian A
BA
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Milbrandt
Jeffrey
J
Johnson
Eugene M
EM
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D029721:Drosophila Proteins; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D020932:Nerve Growth Factor / Q000502:physiology*; D009414:Nerve Growth Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051101:Neurturin; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology*
C490887:Artn protein, rat; D029721:Drosophila Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; C495057:Nrtn protein, rat; D011518:Proto-Oncogene Proteins; C110758:persephin; D020932:Nerve Growth Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C495001:Ret protein, rat