Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth.
Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth.
复制标题
DOI：
10.1016/j.neuron.2011.04.025
复制
发表时间：
2011-06-23
期刊：
影响因子：
16.2
通讯作者：
Kuruvilla R
中科院分区：
文献类型：
--
作者：
Bodmer D;Ascaño M;Kuruvilla R
内吞事件对于神经细胞的存活至关重要，但局部轴突生长是否由内吞依赖的信号机制介导尚不清楚。在这里，我们报道了神经生长因子（NGF）通过钙调磷酸酶介导的内吞gtp酶dynamin1的去磷酸化促进其TrkA受体的内吞和轴突的生长。交感神经元中钙调磷酸酶的条件缺失破坏了周围靶组织的ngf依赖性神经支配。在轴突生长的初始阶段，交感轴突局部需要钙调磷酸酶信号以独立于转录的方式支持ngf介导的生长。我们发现钙调磷酸酶通过PxIxIT相互作用基序与dynamin1结合，该基序仅在特定的dynamin1剪接变体中发现。含有pxixit的dynamin1亚型与表面TrkA受体共定位，它们的磷酸化调控是交感神经元中ngf依赖性TrkA内化和轴突生长所必需的。因此，ngf依赖性的dynamin1磷酸化调控是协调神经营养因子受体内吞作用和初始轴突生长的关键事件。
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, during the initial phase of axonal outgrowth. We show that calcineurin associates with dynamin1 via a PxIxIT interaction motif found only in specific dynamin1 splice variants. PxIxIT-containing dynamin1 isoforms co-localize 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 initial axonal growth.
登录
查看更多内容
影响因子：
16
作者：
Aramburu, J;Garcia-Cozar, F;Hogan, PG
通讯作者：
Hogan, PG
影响因子：
4.8
作者：
Ermak, G;Morgan, TE;Davies, KJA
通讯作者：
Davies, KJA
影响因子：
4.8
作者：
Lai, MM;Hong, JJ;Snyder, SH
通讯作者：
Snyder, SH
影响因子：
64.5
作者：
Graef, IA;Wang, F;Crabtree, GR
通讯作者：
Crabtree, GR
影响因子：
64.5
作者：
Graef, IA;Chen, F;Crabtree, GR
通讯作者：
Crabtree, GR