Activity regulates positive and negative neurotrophin-derived signals to determine axon competition.
Developmental axon competition plays a key role in sculpting neural circuitry. Here, we have asked how activity and neurotrophins could interact to select one axon over another. Using compartmented cultures of sympathetic neurons, we show that, in the presence of NGF, local depolarization confers a competitive growth advantage on the depolarized axon collaterals and at the same time disadvantages the growth of unstimulated axons from the same and competing neurons. Depolarization mediates the competitive advantage by activating a CaMKII-MEK pathway, which converges to enhance local NGF-mediated downstream growth signals. Patterned electrical stimulation also acts via this pathway to enhance NGF-promoted axonal growth. In contrast, the competitive disadvantage is due to BDNF secreted from and acting on the unstimulated, competing axons through p75NTR. Thus, activity regulates both positive and negative neurotrophin-derived signaling cascades to confer a competitive growth advantage on one axon versus another, thereby providing a cellular mechanism for developmental axon selection.
Singh
Karun K
KK
Department of Developmental Biology, Institute of Medical Sciences, University of Toronto, Toronto, M5G 1X8, Canada.
Miller
Freda D
FD
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009434:Neural Pathways / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1