| Literature DB >> 33758193 |
Tomoyuki Yoshida1,2,3, Atsushi Yamagata4, Ayako Imai5, Juhyon Kim6, Hironori Izumi5, Shogo Nakashima7, Tomoko Shiroshima8, Asami Maeda9, Shiho Iwasawa-Okamoto5, Kenji Azechi5, Fumina Osaka10, Takashi Saitoh10, Katsumi Maenaka10,11, Takashi Shimada12, Yuko Fukata13, Masaki Fukata13, Jumpei Matsumoto14,7, Hisao Nishijo14,7, Keizo Takao14,15, Shinji Tanaka16, Shigeo Okabe16, Katsuhiko Tabuchi17,18,19, Takeshi Uemura19,20, Masayoshi Mishina21, Hisashi Mori5,14, Shuya Fukai22.
Abstract
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.Entities:
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Year: 2021 PMID： 33758193 DOI： 10.1038/s41467-021-22059-6
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919