Anatomy, Physiology, and Genetics, Uniformed Services University, Bethesda, Maryland, United States of America.
PLoS One. 2010 Oct 28;5(10):e13709. doi: 10.1371/journal.pone.0013709.
Radial glial cells play an essential role during corticogenesis through their function as neural precursors and guides of neuronal migration. Both reelin and neuregulin1 (NRG1) maintain the radial glial scaffold; they also induce expression of Brain Lipid Binding Protein (BLBP), a well known marker of radial glia. Although radial glia in normal ferrets express both vimentin and BLBP, this coexpression diverges at P3; vimentin is expressed in the radial glial processes, while BLBP appears in cells detached from the ventricular zone. Our lab developed a model of cortical dysplasia in the ferret, resulting in impaired migration of neurons into the cortical plate and disordered radial glia. This occurs after exposure to the antimitotic methylazoxymethanol (MAM) on the 24th day of development (E24). Ferrets treated with MAM on E24 result in an overall decrease of BLBP expression; radial glia that continue to express BLBP, however, show only mild disruption compared with the strongly disrupted vimentin expressing radial glia. When E24 MAM-treated organotypic slices are exposed to reelin or NRG1, the severely disrupted vimentin+ radial glial processes are repaired but the slightly disordered BLBP+ processes are not. The realignment of vimentin+ processes was linked with an increase of their BLBP expression. BLBP expressing radial glia are distinguished by being both less affected by MAM treatment and by attempts at repair. We further investigated the effects induced by reelin and found that signaling was mediated via VLDLR/Dab1/Pi3K activation while NRG1 signaling was mediated via erbB3/erbB4/Pi3K. We then tested whether radial glial repair correlated with improved neuronal migration. Repairing the radial glial scaffold is not sufficient to restore neuronal migration; although reelin improves migration of neurons toward the cortical plate signaling through ApoER2/Dab1/PI3K activation, NRG1 does not.
放射状胶质细胞在皮质发生过程中通过作为神经前体细胞和神经元迁移的指导者发挥重要作用。 两者 reelin 和神经调节蛋白 1（NRG1）维持放射状胶质细胞支架； 它们还诱导 Brain Lipid Binding Protein（BLBP）的表达，BLBP 是放射状胶质细胞的已知标志物。 尽管正常雪貂的放射状胶质细胞表达波形蛋白和 BLBP，但这种共表达在 P3 时发生分歧； 波形蛋白在放射状胶质细胞突起中表达，而 BLBP 出现在与脑室区分离的细胞中。 我们的实验室在雪貂中开发了皮质发育不良模型，导致神经元向皮质板迁移受损和放射状胶质细胞紊乱。 这发生在发育第 24 天（E24）暴露于抗有丝分裂剂甲基偶氮甲醇（MAM）之后。 在 E24 用 MAM 处理的雪貂导致 BLBP 表达总体减少； 然而，与强烈破坏的表达波形蛋白的放射状胶质细胞相比，继续表达 BLBP 的放射状胶质细胞仅显示出轻微的破坏。 当 E24 MAM 处理的器官型切片暴露于 reelin 或 NRG1 时，严重破坏的波形蛋白+放射状胶质细胞突起被修复，但稍微紊乱的 BLBP+过程没有被修复。 波形蛋白+过程的重新排列与它们 BLBP 表达的增加有关。 受 MAM 处理和修复尝试影响较小的表达 BLBP 的放射状胶质细胞被区分开来。 我们进一步研究了 reelin 诱导的影响，发现信号转导通过 VLDLR/Dab1/PI3K 激活介导，而 NRG1 信号转导通过 erbB3/erbB4/PI3K 介导。 然后，我们测试了放射状胶质细胞修复是否与改善神经元迁移相关。 修复放射状胶质细胞支架不足以恢复神经元迁移； 尽管 reelin 通过激活 ApoER2/Dab1/PI3K 改善神经元向皮质板的迁移，但 NRG1 不行。
