Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins

• Published in: Cell reports (Cambridge) 2022-04, Vol.39 (1), p.110624-110624, Article 110624
• Main Authors: Uemura, Takeshi, Suzuki-Kouyama, Emi, Kawase, Shiori, Kurihara, Taiga, Yasumura, Misato, Yoshida, Tomoyuki, Fukai, Shuya, Yamazaki, Maya, Fei, Peng, Abe, Manabu, Watanabe, Masahiko, Sakimura, Kenji, Mishina, Masayoshi, Tabuchi, Katsuhiko
• Format: Article
• Language: English
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Cell Survival; Cells, Cultured; Cerebellum - metabolism; CP: Neuroscience; Ligands; Mice; Mice, Knockout; Neurons - metabolism; Synapses - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110624

Neurexins (NRXNs) are key presynaptic cell adhesion molecules that regulate synapse formation and function via trans-synaptic interaction with postsynaptic ligands. Here, we generate cerebellar granule cell (CGC)-specific Nrxn triple-knockout (TKO) mice for complete deletion of all NRXNs. Unexpectedly, most CGCs die in these mice, and this requirement for NRXNs for cell survival is reproduced in cultured CGCs. The axons of cultured Nrxn TKO CGCs that are not in contact with a postsynaptic structure show defects in the formation of presynaptic protein clusters and in action-potential-induced Ca2+ influxes. These cells also show impaired secretion of depolarization-induced, fluorescence-tagged brain-derived neurotrophic factor (BDNF) from their axons, and the cell-survival defect is rescued by the application of BDNF. These results suggest that CGC survival is maintained by autocrine neurotrophic factors and that NRXNs organize the presynaptic protein clusters and the autocrine neurotrophic-factor secretory machinery independent of contact with postsynaptic ligands. [Display omitted] •Neurexins are essential for cerebellar granule-cell survival•Neurexins regulate cerebellar granule-cell survival independent of PF–PC synapse•Neurexins are essential for axonal neurotrophic-factor secretory machinery•Neurexins are essential for formation of presynaptic-like structures Uemura et al. generate cerebellar granule cell (CGC)-specific Neurexin TKO mice and find that Neurexins are essential for CGC survival. They show that Neurexins organize the presynaptic protein clusters and the autocrine neurotrophic-factor secretory machinery essential for CGC survival independent of contact with postsynaptic ligands.