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

doi:10.1016/j.celrep.2022.110624

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

Cell Rep. 2022 Apr 5;39(1):110624. doi: 10.1016/j.celrep.2022.110624.

Authors

Affiliations

¹ 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. Electronic address: tuemura@shinshu-u.ac.jp.
² Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan; JST CREST, Saitama 332-0012, Japan.
³ 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.
⁴ Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano 390-8621, Japan.
⁵ 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.
⁶ 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.
⁷ JST CREST, Saitama 332-0012, Japan; Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
⁸ Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
⁹ 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.
¹⁰ Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
¹¹ 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.
¹² 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. Electronic address: ktabuchi@shinshu-u.ac.jp.

PMID: 35385735
DOI: 10.1016/j.celrep.2022.110624

Abstract

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.

Keywords: CP: Neuroscience.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain-Derived Neurotrophic Factor* / metabolism
Cell Survival
Cells, Cultured
Cerebellum / metabolism
Ligands
Mice
Mice, Knockout
Neurons* / metabolism
Synapses / metabolism

Substances

Brain-Derived Neurotrophic Factor
Ligands