Sadakata Tetsushi, Kakegawa Wataru, Mizoguchi Akira, Washida Miwa, Katoh-Semba Ritsuko, Shutoh Fumihiro, Okamoto Takehito, Nakashima Hisako, Kimura Kazushi, Tanaka Mika, Sekine Yukiko, Itohara Shigeyoshi, Yuzaki Michisuke, Nagao Soichi, Furuichi Teiichi
Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
J Neurosci. 2007 Mar 7;27(10):2472-82. doi: 10.1523/JNEUROSCI.2279-06.2007.
Ca2+-dependent activator protein for secretion 2 (CAPS2/CADPS2) is a secretory granule-associated protein that is abundant at the parallel fiber terminals of granule cells in the mouse cerebellum and is involved in the release of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), both of which are required for cerebellar development. The human homolog gene on chromosome 7 is located within susceptibility locus 1 of autism, a disease characterized by several cerebellar morphological abnormalities. Here we report that CAPS2 knock-out mice are deficient in the release of NT-3 and BDNF, and they consequently exhibit suppressed phosphorylation of Trk receptors in the cerebellum; these mice exhibit pronounced impairments in cerebellar development and functions, including neuronal survival, differentiation and migration of postmitotic granule cells, dendritogenesis of Purkinje cells, lobulation between lobules VI and VII, structure and vesicular distribution of parallel fiber-Purkinje cell synapses, paired-pulse facilitation at parallel fiber-Purkinje cell synapses, rotarod motor coordination, and eye movement plasticity in optokinetic training. Increased granule cell death of the external granular layer was noted in lobules VI-VII and IX, in which high BDNF and NT-3 levels are specifically localized during cerebellar development. Therefore, the deficiency of CAPS2 indicates that CAPS2-mediated neurotrophin release is indispensable for normal cerebellar development and functions, including neuronal differentiation and survival, morphogenesis, synaptic function, and motor learning/control. The possible involvement of the CAPS2 gene in the cerebellar deficits of autistic patients is discussed.
分泌型钙依赖性激活蛋白2（CAPS2/CADPS2）是一种与分泌颗粒相关的蛋白质，在小鼠小脑颗粒细胞的平行纤维终末中含量丰富，参与神经营养因子-3（NT-3）和脑源性神经营养因子（BDNF）的释放，这两种因子都是小脑发育所必需的。位于7号染色体上的人类同源基因位于自闭症易感基因座1内，自闭症是一种以多种小脑形态异常为特征的疾病。在此我们报告，CAPS2基因敲除小鼠缺乏NT-3和BDNF的释放，因此它们小脑内Trk受体的磷酸化受到抑制；这些小鼠在小脑发育和功能方面表现出明显缺陷，包括有丝分裂后颗粒细胞的神经元存活、分化和迁移、浦肯野细胞的树突形成、小叶VI和VII之间的小叶形成、平行纤维-浦肯野细胞突触的结构和囊泡分布、平行纤维-浦肯野细胞突触处的双脉冲易化、转棒运动协调性以及视动训练中的眼球运动可塑性。在小叶VI-VII和IX中观察到外颗粒层颗粒细胞死亡增加，在小脑发育过程中，BDNF和NT-3水平在这些区域特异性定位。因此，CAPS2的缺乏表明CAPS2介导的神经营养因子释放对于正常的小脑发育和功能是不可或缺的，包括神经元分化和存活、形态发生、突触功能以及运动学习/控制。本文还讨论了CAPS2基因可能与自闭症患者小脑缺陷有关。
