Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice

• Published in: Nature communications Vol. 12; no. 1; pp. 1848 - 15
• Main Authors: Yoshida, Tomoyuki, Yamagata, Atsushi, Imai, Ayako, Kim, Juhyon, Izumi, Hironori, Nakashima, Shogo, Shiroshima, Tomoko, Maeda, Asami, Iwasawa-Okamoto, Shiho, Azechi, Kenji, Osaka, Fumina, Saitoh, Takashi, Maenaka, Katsumi, Shimada, Takashi, Fukata, Yuko, Fukata, Masaki, Matsumoto, Jumpei, Nishijo, Hisao, Takao, Keizo, Tanaka, Shinji, Okabe, Shigeo, Tabuchi, Katsuhiko, Uemura, Takeshi, Mishina, Masayoshi, Mori, Hisashi, Fukai, Shuya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 631/378/2591; 631/378/3919; 631/80/304; 64; 64/60; 82/83; Alternative splicing; Amino Acid Sequence; Animals; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Behavior Rating Scale; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell adhesion; Cell Adhesion Molecules, Neuronal - chemistry; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Disease Models, Animal; Female; HEK293 Cells; Humanities and Social Sciences; Humans; Male; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Motor skill learning; multidisciplinary; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Cell Adhesion Molecules - chemistry; Neural Cell Adhesion Molecules - genetics; Neural Cell Adhesion Molecules - metabolism; Neurons - metabolism; Phosphatase; Protein Domains; Protein Splicing; Protein-tyrosine-phosphatase; Proteins; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - chemistry; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - metabolism; Recombinant Proteins; Science; Science (multidisciplinary); Signal Transduction - genetics; Signal Transduction - physiology; Social Behavior; Splicing; Synapses - genetics; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22059-6

Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality. Mutations of Neuroligin 3 (NLGN3) have been associated with autism spectrum disorder (ASD). Here, the authors identify a previously undescribed interaction between NLGN3 and a splice variant of protein tyrosine phosphatase δ (PTP δ) and its role in development of social behaviour in mice.