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

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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. © 2011 Elsevier Inc.

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Bodmer, D., Ascaño, M., & Kuruvilla, R. (2011). Isoform-Specific Dephosphorylation of Dynamin1 by Calcineurin Couples Neurotrophin Receptor Endocytosis to Axonal Growth. Neuron, 70(6), 1085–1099. https://doi.org/10.1016/j.neuron.2011.04.025

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