Impaired cerebellar functions in mutant mice lacking DNER
Impaired cerebellar functions in mutant mice lacking DNER
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DOI：
10.1016/j.mcn.2005.10.003
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发表时间：
2006-02-01
影响因子：
3.5
通讯作者：
Takeshima, H
中科院分区：
文献类型：
--
作者：
Tohgo, A;Eiraku, M;Takeshima, H
DNER 是一种携带细胞外 EGF 重复序列的跨膜蛋白，在小脑浦肯野细胞 (PC) 中强烈表达。目前的研究表明，DNER 作为一种新的 Notch 配体发挥作用，并通过细胞间相互作用介导功能通讯。通过生产和分析缺乏 DNER 的基因敲除小鼠，我们证明了它在小脑功能和形态成熟中的重要作用。基因敲除小鼠在固定杆和旋转杆测试中表现出运动不协调。基因敲除小鼠的小脑形态发生明显迟缓，裂隙组织持续异常。组织化学和电生理学分析发现，PC 保留了突变小脑中攀爬纤维 (CF) 的多重神经支配。从平行纤维（PF）或 CF 到 PC 的突触传递显然是正常的，而突变小鼠中 PF-PC 突触的谷氨酸清除率显着受损。此外，GLAST（主要在伯格曼胶质细胞（BG）中表达的谷氨酸转运蛋白）的蛋白质水平在突变小脑中降低。我们的结果表明，DNER 通过细胞间通讯参与刺激 BG 成熟，并且对于小脑的精确发育至关重要。 (c) 2005 Elsevier Inc. 保留所有权利。
DNER is a transmembrane protein carrying extracellular EGF repeats and is strongly expressed in Purkinje cells (PCs) in the cerebellum. Current study indicated that DNER functions as a new Notch ligand and mediates the functional communication via cell-cell interaction. By producing and analyzing knockout mice lacking DNER, we demonstrate its essential roles in functional and morphological maturation of the cerebellum. The knockout mice exhibited motor discoordination in the fixed bar and rota-rod tests. The cerebellum from the knockout mice showed significant retardation in morphogenesis and persistent abnormality in fissure organization. Histochemical and electrophysiological analyses detected that PCs retained multiple innervations from climbing fibers (CFs) in the mutant cerebellum. Synaptic transmission from parallel fibers (PFs) or CFs to PCs was apparently normal, while glutamate clearance at the PF-PC synapses was significantly impaired in the mutant mice. Moreover, the protein level of GLAST, the glutamate transporter predominantly expressed in Bergmann glia (BG), was reduced in the mutant cerebellum. Our results indicate that DNER takes part in stimulation of BG maturation via intercellular communication and is essential for precise cerebellar development. (c) 2005 Elsevier Inc. All rights reserved.