TY - JOUR
T1 - Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice
AU - Yoshida, Tomoyuki
AU - Yamagata, Atsushi
AU - Imai, Ayako
AU - Kim, Juhyon
AU - Izumi, Hironori
AU - Nakashima, Shogo
AU - Shiroshima, Tomoko
AU - Maeda, Asami
AU - Iwasawa-Okamoto, Shiho
AU - Azechi, Kenji
AU - Osaka, Fumina
AU - Saitoh, Takashi
AU - Maenaka, Katsumi
AU - Shimada, Takashi
AU - Fukata, Yuko
AU - Fukata, Masaki
AU - Matsumoto, Jumpei
AU - Nishijo, Hisao
AU - Takao, Keizo
AU - Tanaka, Shinji
AU - Okabe, Shigeo
AU - Tabuchi, Katsuhiko
AU - Uemura, Takeshi
AU - Mishina, Masayoshi
AU - Mori, Hisashi
AU - Fukai, Shuya
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102850005&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22059-6
DO - 10.1038/s41467-021-22059-6
M3 - 学術論文
C2 - 33758193
AN - SCOPUS:85102850005
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1848
ER -