Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 444-8787, Japan.
J Neurosci. 2012 May 9;32(19):6468-84. doi: 10.1523/JNEUROSCI.0590-12.2012.
Adenomatous polyposis coli 2 (APC2) is a family member of APC and mainly expressed in the nervous system. We previously reported that APC2 plays a critical role in axonal projection through the regulation of microtubule stability. Here, we show that a lack of Apc2 induces severe laminary defects in some regions of the mouse brain, including the cerebral cortex and cerebellum. In vivo BrdU labeling and immunohistochemical analyses with specific markers revealed that the laminary abnormalities are a result of dysregulated neuronal migration by a cell-autonomous mechanism. Using total internal reflection fluorescent microscopy, we found that APC2 is distributed along actin fibers as well as microtubules. Cerebellar granule cells in dissociated cultures and in vivo showed that BDNF-stimulated directional migration is impaired in Apc2-deficient neurons. We revealed that this impairment stems from the dysregulations of Rho family GTPase activation and TrkB localization, which disrupts the formation of BDNF-stimulated F-actin at the leading edge. Thus, APC2 is an essential mediator of the cytoskeletal regulation at leading edges in response to extracellular signals.
腺瘤性结肠息肉病基因 2（APC2）是 APC 的家族成员，主要在神经系统中表达。我们之前报道过 APC2 通过调节微管稳定性在轴突投射中起关键作用。在这里，我们表明 Apc2 的缺失会在小鼠大脑的一些区域（包括大脑皮层和小脑）中引起严重的层状缺陷。体内 BrdU 标记和特定标志物的免疫组织化学分析表明，层状异常是通过自主机制调节神经元迁移的结果。使用全内反射荧光显微镜，我们发现 APC2 沿肌动蛋白纤维和微管分布。分离培养的小脑颗粒细胞和体内实验表明，BDNF 刺激的定向迁移在 Apc2 缺陷神经元中受损。我们揭示了这种损伤源于 Rho 家族 GTP 酶激活和 TrkB 定位的失调，这破坏了 BDNF 刺激的 F-肌动蛋白在前沿的形成。因此，APC2 是细胞骨架在响应细胞外信号时在前沿的调节的重要介质。
