Analyses of the function of CAPS family proteins in vivo

Ca 2+依赖性分泌激活蛋白2（CAPS 2或CADPS 2）有效促进脑源性神经营养因子（BDNF）的释放。一种罕见的CAPS 2外显子3缺失（dex 3）剪接形式在一些自闭症患者中被发现过度表达。因此，我们产生了Caps 2-dex 3小鼠，并验证了轴突Caps 2-dex 3定位的严重损伤，有助于减少BDNF从轴突释放。此外，通过脊柱和中间神经元密度测量的电路连接性在全球范围内减少。在发育过程中减少轴突BDNF释放的集体效应是一个引人注目的和选择性的赤字在社会和焦虑相关的行为。总之，这些研究结果代表了第一个连接BDNF介导的协调大脑发育的分子机制的小鼠模型，自闭症相关的行为和患者genotype.We发现，体CAPS 2与高尔基体膜，介导结合和招聘的GDP结合形式的ARF 4和ARF 5（膜运输小GT3家族的成员）到高尔基体膜。CAPS 2敲除和CAPS 2结合缺陷型ARF 4/5的过度表达均诱导DCV驻留蛋白嗜铬粒蛋白A（ChgA）在高尔基体周围积累。CAPS 2基因敲除小鼠在电子显微镜下观察时具有扩张的trans-Golgi结构。CAPS 2的这些结果强烈支持我们的想法，即CAPS家族蛋白在DCV运输中发挥双重作用，介导在分泌位点的胞吐和在高尔基复合体的生物合成的运输。

Ca2+-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Therefore, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in social- and anxiety-related behaviors. Together, these findings represent the first mouse model of a molecular mechanism linking BDNF-mediated coordination of brain development to autism-related behaviors and patient genotype.We found that somal CAPS2 is associated with the Golgi membrane, and mediates binding and recruitment of the GDP-bound form of ARF4 and ARF5 (members of the membrane trafficking small GTPase family) to the Golgi membrane. CAPS2 knockdown and over-expression of CAPS2-binding-deficient ARF4/5 both induced accumulation of the DCV resident protein chromogranin A (ChgA) around the Golgi apparatus. CAPS2 knockout mice have dilated trans-Golgi structures when viewed by electron microscopy. These results for CAPS2 strongly support our idea that the CAPS family proteins exert dual roles in DCV trafficking, mediating trafficking at both the secretion site for exocytosis and at the Golgi complex for biogenesis.