Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons.
Axon outgrowth is the first step in the formation of neuronal connections, but the pathways that regulate axon extension are still poorly understood. We find that mice deficient in calcineurin-NFAT signaling have dramatic defects in axonal outgrowth, yet have little or no defect in neuronal differentiation or survival. In vitro, sensory and commissural neurons lacking calcineurin function or NFATc2, c3, and c4 are unable to respond to neurotrophins or netrin-1 with efficient axonal outgrowth. Neurotrophins and netrins stimulate calcineurin-dependent nuclear localization of NFATc4 and activation of NFAT-mediated gene transcription in cultured primary neurons. These data indicate that the ability of these embryonic axons to respond to growth factors with rapid outgrowth requires activation of calcineurin/NFAT signaling by these factors. The precise parsing of signals for elongation turning and survival could allow independent control of these processes during development.
Graef
Isabella A
IA
Department of Developmental Biology, 300 Pasteur Drive, Stanford, CA 94305, USA.
Wang
Fan
F
Charron
Frederic
F
Chen
Lei
L
Neilson
Joel
J
Tessier-Lavigne
Marc
M
Crabtree
Gerald R
GR
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D019703:Calcineurin / Q000172:deficiency* / Q000235:genetics; D065095:Calcineurin Inhibitors; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics; D050778:NFATC Transcription Factors; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D000075388:Netrin-1; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D006133:Growth Substances; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C494007:Nfatc2 protein, mouse; C467907:Nfatc4 protein, mouse; C000617353:Ntn1 protein, mouse; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C445503:transcription factor NF-AT c3; D000075388:Netrin-1; D019703:Calcineurin