Tonic ATP-mediated growth suppression in peripheral nerve glia requires arrestin-PP2 and is evaded in NF1

Robert A Coover,Tabitha E Healy,Katherine E Chaney,Li Guo,Lindsey E Aschbacher-Smith,Michael P Jankowski,Robert F Hennigan,Nancy Ratner,Craig S Thomson

doi:10.1186/s40478-018-0635-9

Robert A Coover, Tabitha E Healy + Show 7 more

Open Access

https://doi.org/10.1186/s40478-018-0635-9

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Abstract

Normal Schwann cells (SCs) are quiescent in adult nerves, when ATP is released from the nerve in an activity dependent manner. We find that suppressing nerve activity in adult nerves causes SC to enter the cell cycle. In vitro, ATP activates the SC G-protein coupled receptor (GPCR) P2Y2. Downstream of P2Y2, β-arrestin-mediated signaling results in PP2-mediated de-phosphorylation of AKT, and PP2 activity is required for SC growth suppression. NF1 deficient SC show reduced growth suppression by ATP, and are resistant to the effects of β-arrestin-mediated signaling, including PP2-mediated de-phosphorylation of AKT. In patients with the disorder Neurofibromatosis type 1, NF1 mutant SCs proliferate and form SC tumors called neurofibromas. Elevating ATP levels in vivo reduced neurofibroma cell proliferation. Thus, the low proliferation characteristic of differentiated adult peripheral nerve may require ongoing, nerve activity-dependent, ATP. Additionally, we identify a mechanism through which NF1 SCs may evade growth suppression in nerve tumors.

Highlights

Schwann cells (SCs) are the supporting glial cells of the peripheral nervous system (PNS)
We find that SC proliferation is modulated by ATP-dependent β-arrestin/PP2A signaling, and that Neurofibromatosis Type 1 (NF1)−/− SCs evade the growth suppressive effects of ATP
Activity-dependent ATP mediates the growth suppression in non-myelinating and myelinating SCs We set out to test the hypothesis that nerve activity, via ATP, is relevant for SC growth suppression in WT nerve in vivo (Fig. 1a)

Summary

Introduction

Schwann cells (SCs) are the supporting glial cells of the peripheral nervous system (PNS). In the adult nerve, specialized cellular domains maintain normal function of the nervous system via bi-directional SC-neuron communication [69]. During nerve development dynamic communication between SC and the neurons with which they associate influences SC-based axon sorting, SC proliferation, and SC differentiation [22, 27, 76]. The developmental proliferation of SC precursors and immature SCs is driven by axonal neuregulin [34]. Perinatal Sox10-positive SCs associated with neuronal axons > 1 μm differentiate, elaborating myelin sheaths that increase axonal conduction velocity. As perinatal SCs differentiate into myelin-forming cells or non-myelinating cells associated with smaller axons, they exit the cell cycle. Perinatal SC proliferation and expression of myelination markers such as myelin basic protein (MBP)

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