Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

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

doi:10.3389/fncel.2019.00518

Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt/mTOR Signaling

Front Cell Neurosci. 2019 Nov 29:13:518. doi: 10.3389/fncel.2019.00518. eCollection 2019.

Authors

Jing Xu^{1

2}, Yong-Lan Du^{1

2}, Jing-Wei Xu^{1

2}, Xiao-Ge Hu³, Lin-Fan Gu⁴, Xiu-Mao Li⁵, Ping-Hong Hu^{1

2}, Tai-Lin Liao^{1

2}, Qiang-Qiang Xia^{1

2}, Qi Sun², Lei Shi⁶, Jian-Hong Luo², Jun Xia^{7

8

9}, Ziyi Wang⁷, Junyu Xu^{1

2}

Affiliations

¹ Department of Rehabilitation of the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
² Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
³ Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
⁴ Zhejiang University-University of Edinburgh Institute, Jiaxing, China.
⁵ Department of Orthopaedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁶ JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Jinan University, Guangzhou, China.
⁷ Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
⁸ Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
⁹ State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.

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.

Keywords: Akt/mTOR; MAGI-2; PTEN; dendritic outgrowth; neuroligin 3.