A model for neuronal competition during development.
We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its own receptor TrkA in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain-derived neurotrophic factor and neurotrophin-4, which, through the receptor p75, can kill neighboring neurons with low retrograde NGF-TrkA signaling whereas neurons with high NGF-TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects.
Deppmann
Christopher D
CD
Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mihalas
Stefan
S
Sharma
Nikhil
N
Lonze
Bonnie E
BE
Niebur
Ernst
E
Ginty
David D
DD
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003198:Computer Simulation; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008433:Mathematics; D051379:Mice; D008959:Models, Neurological; D020932:Nerve Growth Factor / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017783:Superior Cervical Ganglion / Q000166:cytology*
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D020932:Nerve Growth Factor; D020917:Receptor, trkA; C073922:neurotrophin 4