Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins
Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins
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神经毒素通过组织神经营养素的自分泌机制，在小脑颗粒细胞的存活中发挥至关重要的作用
DOI：
10.1016/j.celrep.2022.110624
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发表时间：
2022
期刊：
影响因子：
8.8
通讯作者：
Tabuchi K
中科院分区：
文献类型：
--
作者：
Uemura T;Suzuki-Kouyama E;Kawase S;Kurihara T;Yasumura M;Yoshida T;Fukai S;Yamazaki M;Fei P;Abe M;Watanabe M;Sakimura K;Mishina M;Tabuchi K
神经毒素（NRXN）是突触前细胞粘附的重要分子，通过与突触后配体的相互作用调节突触的形成和功能。在这里，我们产生小脑颗粒细胞（CGC）-特异性NRXN三重敲除（TKO）小鼠完全删除所有NRXN。出乎意料的是，大多数CGC在这些小鼠中死亡，并且细胞存活对NRXN的这种需求在培养的CGC中重现。不与突触后结构接触的culturedNrxnTKO CGCs的轴突在突触前蛋白簇的形成和动作电位诱导的Ca 2+内流中显示出缺陷。这些细胞还显示出从其轴突中分泌去极化诱导的荧光标记的脑源性神经营养因子（BDNF）受损，并且通过应用BDNF来挽救细胞存活缺陷。这些结果表明，CGC的生存是由自分泌的神经营养因子和NRXNs组织突触前蛋白质簇和自分泌的神经营养因子分泌机制独立于接触突触后配体。
Neurexins (NRXNs) are key presynaptic cell adhesion molecules that regulate synapse formation and function viatrans-synaptic interaction with postsynaptic ligands. Here, we generate cerebellar granule cell (CGC)-specificNrxntriple-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 culturedNrxnTKO 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.