Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins
Takeshi Uemura,
Emi Suzuki-Kouyama,
Shiori Kawase,
Taiga Kurihara,
Misato Yasumura,
Tomoyuki Yoshida,
Shuya Fukai,
Maya Yamazaki,
Peng Fei,
Manabu Abe,
Masahiko Watanabe,
Kenji Sakimura,
Masayoshi Mishina,
Katsuhiko Tabuchi
Affiliations
Takeshi Uemura
Division of Gene Research, Research Center for Advanced Science, Shinshu University, Nagano 390-8621, Japan; Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 390-8621, Japan; Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan; Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; JST CREST, Saitama 332-0012, Japan; Corresponding author
Emi Suzuki-Kouyama
Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan; JST CREST, Saitama 332-0012, Japan
Shiori Kawase
Division of Gene Research, Research Center for Advanced Science, Shinshu University, Nagano 390-8621, Japan; Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan; JST CREST, Saitama 332-0012, Japan
Taiga Kurihara
Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan
Misato Yasumura
Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Tomoyuki Yoshida
Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; JST PRESTO, Saitama 332-0012, Japan
Shuya Fukai
JST CREST, Saitama 332-0012, Japan; Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Maya Yamazaki
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Peng Fei
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Manabu Abe
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Masahiko Watanabe
Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
Kenji Sakimura
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
Masayoshi Mishina
Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Brain Science Laboratory, Research Organization of Science and Technology, Ritsumeikan University, Shiga 525-8577, Japan
Katsuhiko Tabuchi
Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano 390-8621, Japan; Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan; JST PRESTO, Saitama 332-0012, Japan; Corresponding author
Summary: 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.
