Constitutive activation of neuronal Src causes aberrant dendritic morphogenesis in mouse cerebellar Purkinje cells
Constitutive activation of neuronal Src causes aberrant dendritic morphogenesis in mouse cerebellar Purkinje cells
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DOI：
10.1016/j.neures.2006.10.007
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发表时间：
2007-02-01
影响因子：
2.9
通讯作者：
Okada, Masato
中科院分区：
文献类型：
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作者：
Kotani, Takenori;Morone, Nobuhiro;Okada, Masato
SRC家族酪氨酸激酶对神经发育至关重要，但由于家族成员之间的功能补偿，它们在体内的功能仍然难以捉摸。为了阐明单个Src家族成员在体内的作用，我们利用U启动子在小脑Purkinje细胞中获得了表达神经元形式的c-Src(n-Src)Fyn及其结构性活性形式的转基因小鼠。结构活性的n-Src的表达延缓了Purkinje细胞的出生后发育，并扰乱了树突状细胞的形态发生，而野生型n-Src的表达只有中等程度的影响。无论是野生型还是结构性活性Fyn过表达都不会显著影响浦肯野细胞的形态。在n-Src转基因小鼠中，异常的浦肯野细胞保留了沿非极化方向延伸的多个树突状突起，并异位位于分子层。超微结构观察显示，n-Src转基因小鼠的微管密度较高，排列规则，结构畸形。在原代培养中，来自n-Src转基因小鼠的Purkinje细胞出现异常粗大的树突轴和大的生长锥状结构，树突伸展不良，这可以通过选择性的Src家族激酶抑制剂PP2来挽救。这些结果表明，n-Src活性通过影响微管组织来调节浦肯野细胞的树突状形态发生。(C)2006年爱思唯尔爱尔兰有限公司和日本神经科学学会。版权所有。
Src family tyrosine kinases are essential for neural development, but their in vivo functions remain elusive because of functional compensation among family members. To elucidate the roles of individual Src family members in vivo, we generated transgenic mice expressing the neuronal form of c-Src (n-Src), Fyn, and their constitutively active forms in cerebellar Purkinje cells using the U promoter. The expression of the constitutively active n-Src retarded the postnatal development of Purkinje cells and disrupted dendritic morphogenesis, whereas the wild-type n-Src had only moderate effects. Neither wild-type nor constitutively active Fyn over-expression significantly affected Purkinje-cell morphology. The aberrant Purkinje cells in n-Src transgenic mice retained multiple dendritic shafts extending in non-polarized directions and were located heterotopically in the molecular layer. Ultrastructural observation of the dendritic shafts revealed that the microtubules of n-Src transgenic mice were more densely and irregularly arranged, and had structural deformities. In primary culture, Purkinje cells from n-Src transgenic mice developed abnormally thick dendritic shafts and large growth-cone-like structures with poorly extended dendrites, which could be rescued by treatment with a selective inhibitor of Src family kinases, PP2. These results suggest that n-Src activity regulates the dendritic morphogenesis of Purkinje cells through affecting microtubule organization. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.