Tabata Hidenori, Nakajima Kazunori
Department of Molecular Neurobiology, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
J Neurosci Res. 2002 Sep 15;69(6):723-30. doi: 10.1002/jnr.10345.
The Reelin molecule plays a fundamental role in corticogenesis. After Reelin binds to its receptors, the Reelin signal is transduced through tyrosine phosphorylation of the intracellular adaptor protein disabled 1 (Dab1). The reelin-gene-deficient mouse, reeler, and Dab1-deficient mouse, yotari, show disrupted positioning of neurons. Several molecules have been identified recently as being involved in Reelin signaling, however, the biological function of Reelin during cortical plate development was still unknown. We observed the migrating behavior of neurons during development in Reelin-signal-deficient mice. To visualize the migrating neurons directly, we introduced green fluorescent protein (GFP)-expression vectors into the ventricular zone with an in utero electroporation system and allowed the embryos to develop in utero until they were analyzed. The result showed that the migrating cells in the mutants were morphologically indistinguishable from those of normal mice. At the stage when the GFP-expressing cells reached the marginal zone near the pial surface and began dendrite formation in normal mice, the GFP-positive cells were found at various deeper positions in the mutant cortex. They had the morphology of migrating cells extending leading processes toward the pial surface. By contrast, in the mutants these cells tended to stop migration along the borders of the internal plexiform zone, the irregular structure consisting mainly of dendrites in the mutant cortex. Postnatally, these neurons began to develop dendrites later than the cells in the normal cortex. During this process, some neurons above the internal plexiform zone extended and developed dendrites in the opposite direction into the internal plexiform zone. These results suggest that the abnormal positioning of neurons in the Reelin-signal-deficient mice is caused, at least in part, by abnormal formation of the internal plexiform zone in the mutant cortex.
Reelin分子在皮质发生过程中发挥着重要作用。Reelin与其受体结合后，通过细胞内衔接蛋白失活1（Dab1）的酪氨酸磷酸化来转导Reelin信号。Reelin基因缺陷小鼠reeler和Dab1缺陷小鼠yotari表现出神经元定位紊乱。最近已鉴定出几种参与Reelin信号传导的分子，然而，Reelin在皮质板发育过程中的生物学功能仍然未知。我们观察了Reelin信号缺陷小鼠发育过程中神经元的迁移行为。为了直接观察迁移的神经元，我们使用子宫内电穿孔系统将绿色荧光蛋白（GFP）表达载体导入脑室区，并让胚胎在子宫内发育直至进行分析。结果表明，突变体中的迁移细胞在形态上与正常小鼠的迁移细胞没有区别。在正常小鼠中，表达GFP的细胞到达软脑膜表面附近的边缘区并开始形成树突的阶段，在突变体皮质的不同较深位置发现了GFP阳性细胞。它们具有迁移细胞的形态，向软脑膜表面延伸引导突起。相比之下，在突变体中，这些细胞倾向于在主要由突变体皮质中的树突组成的不规则结构——内丛状带的边界处停止迁移。出生后，这些神经元比正常皮质中的细胞更晚开始形成树突。在此过程中，内丛状带上方的一些神经元向相反方向延伸并在内丛状带中发育树突。这些结果表明，Reelin信号缺陷小鼠中神经元的异常定位至少部分是由突变体皮质内丛状带的异常形成引起的。
