Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / genetics
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Animals
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Calcineurin / deficiency*
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Calcineurin / genetics
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Calcineurin Inhibitors
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Growth Cones / drug effects
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Growth Substances / metabolism
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Growth Substances / pharmacology
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Mice
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Mutation / genetics
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NFATC Transcription Factors
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Nerve Growth Factors / metabolism
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Nerve Growth Factors / pharmacology
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Nervous System / cytology
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Nervous System / embryology*
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Nervous System / metabolism
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Netrin-1
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Nuclear Proteins*
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Protein Synthesis Inhibitors / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Proteins
Substances
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Calcineurin Inhibitors
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DNA-Binding Proteins
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Growth Substances
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NFATC Transcription Factors
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NFATC4 protein, human
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NTN1 protein, human
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Nerve Growth Factors
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Nfatc2 protein, mouse
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Nfatc4 protein, mouse
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Ntn1 protein, mouse
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Nuclear Proteins
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Protein Synthesis Inhibitors
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Transcription Factors
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Tumor Suppressor Proteins
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transcription factor NF-AT c3
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Netrin-1
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Calcineurin