Dataset Information

Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors.

ABSTRACT: Axonal targeting of signaling receptors is essential for neuronal responses to extracellular cues. Here, we report that retrograde signaling by target-derived nerve growth factor (NGF) is necessary for soma-to-axon transcytosis of TrkA receptors in sympathetic neurons, and we define the molecular underpinnings of this positive feedback regulation that enhances neuronal sensitivity to trophic factors. Activated TrkA receptors are retrogradely transported in signaling endosomes from distal axons to cell bodies, where they are inserted on soma surfaces and promote phosphorylation of resident naive receptors, resulting in their internalization. Endocytosed TrkA receptors are then dephosphorylated by PTP1B, an ER-resident protein tyrosine phosphatase, prior to axonal transport. PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a "gatekeeper" mechanism that ensures targeting of inactive receptors to axons to engage with ligand. In mice, PTP1B deletion reduces axonal TrkA levels and attenuates neuron survival and target innervation under limiting NGF (NGF+/-) conditions.

SUBMITTER: Yamashita N

PROVIDER: S-EPMC5614868 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors.

Yamashita Naoya N Joshi Rajshri R Zhang Sheng S Zhang Zhong-Yin ZY Kuruvilla Rejji R

Developmental cell 20170914 6

Axonal targeting of signaling receptors is essential for neuronal responses to extracellular cues. Here, we report that retrograde signaling by target-derived nerve growth factor (NGF) is necessary for soma-to-axon transcytosis of TrkA receptors in sympathetic neurons, and we define the molecular underpinnings of this positive feedback regulation that enhances neuronal sensitivity to trophic factors. Activated TrkA receptors are retrogradely transported in signaling endosomes from distal axons t ...[more]

PMID: 28919207

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Project description:Coincidence detector neurons transmit timing information by responding preferentially to concurrent synaptic inputs. Principal cells of the medial superior olive (MSO) in the mammalian auditory brainstem are superb coincidence detectors. They encode sound source location with high temporal precision, distinguishing submillisecond timing differences among inputs. We investigate computationally how dynamic coupling between the input region (soma and dendrite) and the spike-generating output region (axon and axon initial segment) can enhance coincidence detection in MSO neurons. To do this, we formulate a two-compartment neuron model and characterize extensively coincidence detection sensitivity throughout a parameter space of coupling configurations. We focus on the interaction between coupling configuration and two currents that provide dynamic, voltage-gated, negative feedback in subthreshold voltage range: sodium current with rapid inactivation and low-threshold potassium current, IKLT. These currents reduce synaptic summation and can prevent spike generation unless inputs arrive with near simultaneity. We show that strong soma-to-axon coupling promotes the negative feedback effects of sodium inactivation and is, therefore, advantageous for coincidence detection. Furthermore, the feedforward combination of strong soma-to-axon coupling and weak axon-to-soma coupling enables spikes to be generated efficiently (few sodium channels needed) and with rapid recovery that enhances high-frequency coincidence detection. These observations detail the functional benefit of the strongly feedforward configuration that has been observed in physiological studies of MSO neurons. We find that IKLT further enhances coincidence detection sensitivity, but with effects that depend on coupling configuration. For instance, in models with weak soma-to-axon and weak axon-to-soma coupling, IKLT in the axon enhances coincidence detection more effectively than IKLT in the soma. By using a minimal model of soma-to-axon coupling, we connect structure, dynamics, and computation. Although we consider the particular case of MSO coincidence detectors, our method for creating and exploring a parameter space of two-compartment models can be applied to other neurons.

Dataset Information

Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors.

Publications

Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors.

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