Activated c-Jun N-terminal kinase is required for axon formation.
A critical transition in neuron development is formation of the axon, which establishes the polarized structure of the neuron that underlies its entire input and output capabilities. The morphological events that occur during axonogenesis have long been known, yet the molecular determinants underlying axonogenesis remain poorly understood. We demonstrate here that axonogenesis requires activated c-Jun N-terminal kinase (JNK). JNK is expressed throughout the neuron, but its phosphorylated, activated form is highly enriched in the axon. In young axons, activated JNK forms a proximodistal gradient of increasing intensity, beginning at about the point where the axon exceeds the lengths of the other neurites (minor processes). Treatment with SP600125, a specific inhibitor of JNK, reversibly inhibits axonogenesis but does not prevent the formation of minor processes or their differentiation into dendrites (based on their immunostaining with marker proteins). Expression of a dominant-negative construct against JNK similarly prevents axonogenesis. Investigation of JNK targets revealed that activating transcription factor-2 is phosphorylated under normal conditions in neurons, and its phosphorylation is significantly attenuated after JNK inhibition. These results demonstrate that activated JNK is required for axonogenesis but not formation of minor processes or development of dendrites.
Oliva
Anthony A
AA
Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon 97239, USA. aoliva@miamiproject.med.miami.edu
Atkins
Coleen M
CM
Copenagle
Lily
L
Banker
Gary A
GA
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000201:enzymology / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D006624:Hippocampus / Q000196:embryology* / Q000201:enzymology*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016875:tau Proteins / Q000378:metabolism
D051698:Activating Transcription Factor 2; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases