Expression and regulation of FRMD6 in mouse DRG neurons and spinal cord after nerve injury

Chuang Lyu,Tie-Jun Sten Shi,Gong-Wei Lyu,Jan Mulder,Mathias Uhlén,Xue-Hui Cai,Tomas Hökfelt

doi:10.1038/s41598-020-58261-7

Abstract

FRMD6, a member of the group of FERM-domain proteins, is involved both in communication between cells, interactions with extracellular matrix, cellular apoptotic and regenerative mechanisms. FRMD6 was first discovered in the rodent sciatic nerve, and in the present immunohistochemical study we investigated the distribution of FRMD6 in the dorsal root ganglia (DRGs), sciatic nerve and spinal cord following sciatic nerve injury. FRMD6-immunoreactivity was found in the cytoplasm, nucleus or both, and in a majority of DRG neurons. FRMD6-immunoreactivity co-existed with several well-known neuronal markers, including calcitonin gene-related peptide, isolectin B4 and neurofilament 200 in mouse DRGs. After peripheral nerve injury, the FRMD6 mRNA levels and the overall percentage of FRMD6-positive neuron profiles (NPs) were decreased in ipsilateral lumbar DRGs, the latter mainly affecting small size neurons with cytoplasmic localization. Conversely, the proportion of NPs with nuclear FRMD6-immunoreactivity was significantly increased. In the sciatic nerve, FRMD6-immunoreactivity was observed in non-neuronal cells and in axons, and accumulated proximally to a ligation of the nerve. In the spinal cord FRMD6-immunoreactivity was detected in neurons in both dorsal and ventral horns, and was upregulated in ipsilateral dorsal horn after peripheral nerve axotomy. Our results demonstrate that FRMD6 is strictly regulated by peripheral nerve injury at the spinal level.

Highlights

FRMD 6, known as Willin, is a member of the 4.1 superfamily and was first identified in the sciatic nerve of rats by northern blot analysis[1]
Our findings indicated that the expression of FRMD6 protein and mRNA was overall significantly downregulated by peripheral nerve injury in the dorsal root ganglion (DRG), whereas the protein was significantly upregulated in the spinal dorsal horn
Expression of FRMD6 mRNA has previously been reported in fibroblasts and Schwann cells in the rat sciatic nerve using in situ hybridization[1,13]

Summary

Introduction

FRMD (protein 4.1, ezrin, radixin and moesin) 6, known as Willin, is a member of the 4.1 superfamily and was first identified in the sciatic nerve of rats by northern blot analysis[1]. FRMD6/Ex, as an upstream regulator, is a component of multiple upstream molecular complexes in the Salvador/ Warts/Hippo (Hippo) signaling pathway network that, mostly via MST1/2 (mammalian STE20-like protein kinase) and LATS1/2 (large tumour suppressor homolog), regulates the activity of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), two downstream homologous transcriptional co-activators[5,6,7,8] This pathway, originally identified in drosophila[9,10] and more recently shown to be well conserved in mammalians[11], regulates cellular proliferation, differentiation, apoptosis and tissue homoeostasis[5,6]. Our findings indicated that the expression of FRMD6 protein and mRNA was overall significantly downregulated by peripheral nerve injury in the DRGs, whereas the protein was significantly upregulated in the spinal dorsal horn These data shed a new light on the relationship between sensory neuronal Hippo signaling pathway and peripheral nerve injury

Methods

Results

Conclusion