Graphene Oxide Dysregulates Neuroligin/NLG-1-Mediated Molecular Signaling in Interneurons in Caenorhabditis elegans

He Chen,Huirong Li,Dayong Wang

doi:10.1038/srep41655

Abstract

Graphene oxide (GO) can be potentially used in many medical and industrial fields. Using assay system of Caenorhabditis elegans, we identified the NLG-1/Neuroligin-mediated neuronal signaling dysregulated by GO exposure. In nematodes, GO exposure significantly decreased the expression of NLG-1, a postsynaptic cell adhesion protein. Loss-of-function mutation of nlg-1 gene resulted in a susceptible property of nematodes to GO toxicity. Rescue experiments suggested that NLG-1 could act in AIY interneurons to regulate the response to GO exposure. In the AIY interneurons, PKC-1, a serine/threonine protein kinase C (PKC) protein, was identified as the downstream target for NLG-1 in the regulation of response to GO exposure. LIN-45, a Raf protein in ERK signaling pathway, was further identified as the downstream target for PKC-1 in the regulation of response to GO exposure. Therefore, GO may dysregulate NLG-1-mediated molecular signaling in the interneurons, and a neuronal signaling cascade of NLG-1-PKC-1-LIN-45 was raised to be required for the control of response to GO exposure. More importantly, intestinal RNAi knockdown of daf-16 gene encoding a FOXO transcriptional factor in insulin signaling pathway suppressed the resistant property of nematodes overexpressing NLG-1 to GO toxicity, suggesting the possible link between neuronal NLG-1 signaling and intestinal insulin signaling in the regulation of response to GO exposure.

Highlights

Graphene oxide (GO) can be potentially used in many medical and industrial fields
After GO (1 mg/L) exposure, among the examined 35 genes expressed in the AIY interneurons, we found that mutation of nlg-1 gene significantly decreased the expression levels of abi-1, ceh-23, ptp-3, pkc-1, and ttx-3 (Fig. 4)
Considering the fact that ttx-3, ceh-23, and ptp-3 genes are required for the cell fate specification of AIY interneurons or the presynaptic differentiation in C. elegans[38,39], we examined whether ABI-1 and protein kinase C (PKC)-1 are involved in the control of response to GO exposure

Summary

Introduction

Graphene oxide (GO) can be potentially used in many medical and industrial fields. Using assay system of Caenorhabditis elegans, we identified the NLG-1/Neuroligin-mediated neuronal signaling dysregulated by GO exposure. Some important signaling pathways, such as c-Jun N-terminal kinase (JNK), insulin, p38 mitogen-activated protein kinase (MAPK), Wnt, oxidative stress associated, apoptosis, and DNA damage signaling pathways, have been further identified to be involved in the regulation of GO toxicity in nematodes[22,23,24,25,26,27,28,29,30]. Besides these signaling pathways, some microRNAs (miRNAs), such as mir-231 and mir-360, were shown to participate in the control of GO toxicity in nematodes[23,26,31]. Our results provide the important molecular basis for NLG-1-mediated neuronal signaling in the regulation of response to GO exposure in organisms

Methods

Results

Conclusion