Isoform-Specific Dephosphorylation of Dynamin1 by Calcineurin Couples Neurotrophin Receptor Endocytosis to Axonal Growth

Endocytic events are critical for neuronal survival in response to target-derived neurotrophic cues, but whether local axon growth is mediated by endocytosis-dependent signaling mechanisms remains unclear. Here, we report that Nerve Growth Factor (NGF) promotes endocytosis of its TrkA receptors and...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2011-06, Vol.70 (6), p.1085-1099
Main Authors: Bodmer, Daniel, Ascaño, Maria, Kuruvilla, Rejji
Format: Article
Language:English
Subjects:
Adenoviruses
Alternative splicing
Animals
Axons - metabolism
Calcineurin - metabolism
Confidence intervals
Dynamin I - metabolism
Endocytosis - physiology
Gene expression
Mice
Mice, Knockout
Mice, Transgenic
Nerve Growth Factor - physiology
Neurons
Phosphorylation
Protein Interaction Domains and Motifs - physiology
Protein Isoforms - metabolism
Proteins
Receptor, trkA - metabolism
Rodents
Signal Transduction - physiology
Sympathetic Nervous System - growth & development
Sympathetic Nervous System - metabolism
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Summary:Endocytic events are critical for neuronal survival in response to target-derived neurotrophic cues, but whether local axon growth is mediated by endocytosis-dependent signaling mechanisms remains unclear. Here, we report that Nerve Growth Factor (NGF) promotes endocytosis of its TrkA receptors and axon growth by calcineurin-mediated dephosphorylation of the endocytic GTPase dynamin1. Conditional deletion of calcineurin in sympathetic neurons disrupts NGF-dependent innervation of peripheral target tissues. Calcineurin signaling is required locally in sympathetic axons to support NGF-mediated growth in a manner independent of transcription. We show that calcineurin associates with dynamin1 via a PxIxIT interaction motif found only in specific dynamin1 splice variants. PxIxIT-containing dynamin1 isoforms colocalize with surface TrkA receptors, and their phosphoregulation is selectively required for NGF-dependent TrkA internalization and axon growth in sympathetic neurons. Thus, NGF-dependent phosphoregulation of dynamin1 is a critical event coordinating neurotrophin receptor endocytosis and axonal growth. ► Local calcineurin signaling in axons supports NGF-mediated growth ► NGF promotes dephosphorylation of dynamin1 via calcineurin ► Calcineurin interacts specifically with dynamin1 splice variants with a PxIxIT motif ► Dephosphorylation of dynamin variants regulates TrkA endocytosis and axon growth
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2011.04.025