Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling.

Jing Xu,Lin-Fan Gu,Xiu-Mao Li,Ziyi Wang,Jian-Hong Luo,Lei Shi,Jing-Wei Xu,Xiao-Ge Hu,Junyu Xu,Yong-Lan Du,Tai-Lin Liao,Qi Sun,Qiang-Qiang Xia,Jun Xia,Ping-Hong Hu

doi:10.3389/fncel.2019.00518

Abstract

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the central nervous system. However, the detailed mechanism is still unclear. In our study, we found that deficiency of NL3 led to morphological changes of the pyramidal neurons in layer II/III somatosensory cortex in mice, including enlarged somata, elongated dendritic length, and increased dendritic complexity. Knockdown of NL3 in cultured rat neurons upregulated Akt/mTOR signaling, resulting in both increased protein synthesis and dendritic growth. Treating neurons with either rapamycin to inhibit the mTOR or LY294002 to inhibit the PI3K/Akt activity rescued the morphological abnormalities resulting from either NL3 knockdown or knockout (KO). In addition, we found that the hyperactivated Akt/mTOR signaling associated with NL3 defects was mediated by a reduction in phosphatase and tensin (PTEN) expression, and that MAGI-2, a scaffold protein, interacted with both NL3 and PTEN and could be a linker between NL3 and Akt/mTOR signaling pathway. In conclusion, our results suggest that NL3 regulates neuronal morphology, especially dendritic outgrowth, by modulating the PTEN/Akt/mTOR signaling pathway, probably via MAGI-2. Thereby, this study provides a new link between NL3 and neuronal morphology.

Highlights

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that play a crucial role in synaptogenesis and synaptic transmission (Scheiffele et al, 2000; Dean et al, 2003; Chih et al, 2005)
We show that neuroligin 3 (NL3) regulates the outgrowth of neuronal dendrites by modulating Akt/mammalian target of rapamycin (mTOR) signaling pathway, and the association between NL3 and Akt/mTOR signaling pathway is mediated by phosphatase and tensin (PTEN), probably via MAGI-2,a membrane associated guanylate kinase previously known to bind with NL1 (Hirao et al, 1998) and NL2 (Sumita et al, 2007)
The results demonstrated that NL2 knockdown did not overactivate Akt/mTOR pathway, and reduced the phosphorylation of Akt at Thr308 site, which indicated that the upregulation of Akt/mTOR in NL3 knockdown neurons was not induced by RNAi itself

Summary

Introduction

Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that play a crucial role in synaptogenesis and synaptic transmission (Scheiffele et al, 2000; Dean et al, 2003; Chih et al, 2005). Developmental abnormalities of neuronal dendrites, either over- or under-development, were verified to contribute to multiple mental disorders, including ASD (Kwan et al, 2016; Montani et al, 2017; Dang et al, 2018). Different molecular mechanisms have been indicated to regulate the dendritic outgrowth in the past few decades, including neurotrophic factors (McAllister et al, 1995, 1997) and neurotrophic factor stimulated signaling pathways, such as the mammalian target of rapamycin (mTOR) pathway (Jaworski et al, 2005; Kumar et al, 2005; Urbanska et al, 2012) and extracellular signalregulated kinases (ERK) pathway (Alonso, 2004; Zhang et al, 2014). Whether abnormal dendritic growth occurs in NL3-deficient mice and whether NL3 is involved in the molecular pathways regulating dendritic outgrowth, such as mTOR pathway, are still unknown

Methods

Results

Conclusion