Leucine-Rich Glioma Inactivated 1 Promotes Oligodendrocyte Differentiation and Myelination via TSC-mTOR Signaling.

Ya-Jun Xie,Chong-Yu Shao,Yin Wang,Xiang-Yao Li,Liang Zhou,Lin Zhou,Ying Shen,Nan-Wei Jiang,Shenglong Cao,Xin-Tai Wang

doi:10.3389/fnmol.2018.00231

Abstract

Leucine-rich glioma inactivated 1 (Lgi1), a putative tumor suppressor, is tightly associated with autosomal dominant lateral temporal lobe epilepsy (ADLTE). It has been shown that Lgi1 regulates the myelination of Schwann cells in the peripheral nervous system (PNS). However, the function and underlying mechanisms for Lgi1 regulation of oligodendrocyte differentiation and myelination in the central nervous system (CNS) remain elusive. In addition, whether Lgi1 is required for myelin maintenance is unknown. Here, we show that Lgi1 is necessary and sufficient for the differentiation of oligodendrocyte precursor cells and is also required for the maintenance of myelinated fibers. The hypomyelination in Lgi1−/− mice attributes to the inhibition of the biosynthesis of lipids and proteins in oligodendrocytes (OLs). Moreover, we found that Lgi1 deficiency leads to a decrease in expression of tuberous sclerosis complex 1 (TSC1) and activates mammalian target of rapamycin signaling. Together, the present work establishes that Lgi1 is a regulator of oligodendrocyte development and myelination in CNS.

Highlights

Leucine-rich glioma inactivated 1 (Lgi1), containing a leucine-rich repeat (LRR) domain, encodes a secreted protein in the central nervous system (CNS; Gu et al, 2002)
We show that Lgi1 is necessary and sufficient to the differentiation of oligodendrocyte precursor cells (OPCs) and myelination and is required for the maintenance of myelinated fibers facing cuprizone challenge
We further show that Lgi1 deficiency decreases the expression of tuberous sclerosis complex 1 (TSC1) and breaks the balance of mTOR signaling in OLs, which might be the cause of hypomyelination

Summary

Introduction

Leucine-rich glioma inactivated 1 (Lgi1), containing a leucine-rich repeat (LRR) domain, encodes a secreted protein in the central nervous system (CNS; Gu et al, 2002). Further studies indicate that Lgi is critical to the pruning of glutamatergic synapses in the hippocampus (Zhou et al, 2009) through the interaction with ADAM (a disintegrin and metalloproteinase; Fukata et al, 2006; Chabrol et al, 2010; Thomas et al, 2010). The deletion or mutation in Lgi impairs glutamatergic transmission in hippocampus, which is considered to be the pathologic basis for ADLTE (Fukata et al, 2010; Yu et al, 2010). Apart from epileptogenesis, it has been shown that Lgi plays roles in neuronal and glial development. The ablation of Lgi causes a subtle neuronal dyslamination in the cortex (Silva et al, 2015) and reduces the thickness of external granule cell layer in embryonic cerebellum (CB; Su et al, 2015; Xie et al, 2015). Members of Lgi family are yet involved in the myelination of

Methods

Results

Conclusion