title: Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth.
abstract: 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.
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bodmer
authors.forename: Maria
authors.initials: M
authors.lastname: Ascaño
authors.forename: Rejji
authors.initials: R
authors.lastname: Kuruvilla
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D034284:Dynamin I / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000502:physiology*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013564:Sympathetic Nervous System / Q000254:growth & development / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019703:Calcineurin; D034284:Dynamin I