Caspr Controls the Temporal Specification of Neural Progenitor Cells through Notch Signaling in the Developing Mouse Cerebral Cortex
Caspr Controls the Temporal Specification of Neural Progenitor Cells through Notch Signaling in the Developing Mouse Cerebral Cortex
复制标题
DOI：
10.1093/cercor/bhv318
复制
发表时间：
2016-01
期刊：
影响因子：
3.7
通讯作者：
Zhi-Qiang Wu;Di Li;Ya Huang;Xi-Ping Chen;Wenhui Huang;Chun-feng Liu;He-qing Zhao;Ru-Xiang Xu;Mei Cheng;M. Schachner;Quan-Hong Ma
中科院分区：
文献类型：
--
作者：
Zhi-Qiang Wu;Di Li;Ya Huang;Xi-Ping Chen;Wenhui Huang;Chun-feng Liu;He-qing Zhao;Ru-Xiang Xu;Mei Cheng;M. Schachner;Quan-Hong Ma
在大脑皮层发育过程中，放射状胶质细胞产生层特异性神经元和星形胶质细胞遵循一个精确的时间序列，该序列受内在和外在因素的调节。控制层特异性神经元和星形胶质细胞及时生成的分子机制尚不完全清楚。在这项研究中，我们发现粘附分子接触蛋白（Caspr）参与髓鞘轴突极化区域的维持，对发育中的小鼠大脑皮层神经元和星形胶质细胞的生成时间至关重要。Caspr由放射状胶质细胞表达，放射状胶质细胞是神经祖细胞，可产生神经元和星形胶质细胞。神经祖细胞中Caspr缺失可延缓皮质神经元的产生，诱导皮质星形胶质细胞的早熟形成，但不影响祖细胞的数量。在分子水平上，Caspr与Notch的胞内结构域协同抑制Notch效应物Hes1的转录。通过Hes1 shRNA抑制Notch信号可以挽救Caspr‐缺陷小鼠的异常神经发生和星形发生。这些发现表明Caspr是一种新的关键调节因子，通过Notch信号传导控制发育中的大脑皮层径向胶质细胞的细胞命运的时间规范。
Abstract The generation of layer‐specific neurons and astrocytes by radial glial cells during development of the cerebral cortex follows a precise temporal sequence, which is regulated by intrinsic and extrinsic factors. The molecular mechanisms controlling the timely generation of layer‐specific neurons and astrocytes remain not fully understood. In this study, we show that the adhesion molecule contactin‐associated protein (Caspr), which is involved in the maintenance of the polarized domains of myelinated axons, is essential for the timing of generation of neurons and astrocytes in the developing mouse cerebral cortex. Caspr is expressed by radial glial cells, which are neural progenitor cells that generate both neurons and astrocytes. Absence of Caspr in neural progenitor cells delays the production cortical neurons and induces precocious formation of cortical astrocytes, without affecting the numbers of progenitor cells. At the molecular level, Caspr cooperates with the intracellular domain of Notch to repress transcription of the Notch effector Hes1. Suppression of Notch signaling via a Hes1 shRNA rescues the abnormal neurogenesis and astrogenesis in Caspr‐deficient mice. These findings establish Caspr as a novel key regulator that controls the temporal specification of cell fate in radial glial cells of the developing cerebral cortex through Notch signaling.