Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth

Neuron. 2011 Jun 23;70(6):1085-99. doi: 10.1016/j.neuron.2011.04.025.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Calcineurin / metabolism*
  • Dynamin I / metabolism*
  • Endocytosis / physiology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Growth Factor / physiology*
  • Phosphorylation
  • Protein Interaction Domains and Motifs / physiology
  • Protein Isoforms / metabolism
  • Receptor, trkA / metabolism*
  • Signal Transduction / physiology
  • Sympathetic Nervous System / growth & development
  • Sympathetic Nervous System / metabolism


  • Protein Isoforms
  • Nerve Growth Factor
  • Receptor, trkA
  • Calcineurin
  • Dynamin I