Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain.
Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain.
复制标题
DOI：
--
复制
发表时间：
1998-09
期刊：
影响因子：
4.6
通讯作者：
D. Rice;M. Sheldon;G. D’Arcangelo;K. Nakajima;D. Goldowitz;T. Curran
中科院分区：
文献类型：
--
作者：
D. Rice;M. Sheldon;G. D’Arcangelo;K. Nakajima;D. Goldowitz;T. Curran
reelin (Reln) 或disabled-1 (Dab1) 的突变会导致整个大脑的层状结构普遍异常，并导致 reeler 和 scrambler 小鼠出现共济失调。两者都表现出相同的神经解剖学缺陷，包括小脑发育不全伴浦肯野细胞异位以及大脑皮层和海马神经元层的破坏。尽管有这些表型相似之处，Reln 和 Dab1 仍具有不同的分子特性。 Reln 是一种大型细胞外蛋白，由前脑中的 Cajal-Retzius 细胞和小脑中的颗粒神经元分泌。相比之下，Dab1 是一种细胞质蛋白，具有在磷酸化依赖性细胞内信号转导中发挥作用的衔接蛋白的特性。在这里，我们表明 Dab1 参与与 Reln 相同的发育过程。在扰乱小鼠中，神经元前体无法侵入大脑皮层的前板，因此它们不会在皮层板内对齐。在发育过程中，在大脑皮层、小脑和海马形成的关键阶段，在细胞位置的第一次异常在 reeler 或 scrambler 中变得明显之前，表达 Dab1 的细胞位于分泌 Reln 的细胞旁边。在 reeler 中，主要的移位神经元群体含有升高水平的 Dab1 蛋白，尽管它们表达正常水平的 Dab1 mRNA。这表明 Dab1 在没有 Reln 诱发信号的情况下积累。总而言之，这些结果表明 Dab1 在 Reln 下游的信号通路中发挥作用，控制发育中大脑中的细胞定位。
Mutation of either reelin (Reln) or disabled-1 (Dab1) results in widespread abnormalities in laminar structures throughout the brain and ataxia in reeler and scrambler mice. Both exhibit the same neuroanatomical defects, including cerebellar hypoplasia with Purkinje cell ectopia and disruption of neuronal layers in the cerebral cortex and hippocampus. Despite these phenotypic similarities, Reln and Dab1 have distinct molecular properties. Reln is a large extracellular protein secreted by Cajal-Retzius cells in the forebrain and by granule neurons in the cerebellum. In contrast, Dab1 is a cytoplasmic protein which has properties of an adapter protein that functions in phosphorylation-dependent intracellular signal transduction. Here, we show that Dab1 participates in the same developmental process as Reln. In scrambler mice, neuronal precursors are unable to invade the preplate of the cerebral cortex and consequently, they do not align within the cortical plate. During development, cells expressing Dab1 are located next to those secreting Reln at critical stages of formation of the cerebral cortex, cerebellum and hippocampus, before the first abnormalities in cell position become apparent in either reeler or scrambler. In reeler, the major populations of displaced neurons contain elevated levels of Dab1 protein, although they express normal levels of Dab1 mRNA. This suggests that Dab1 accumulates in the absence of a Reln-evoked signal. Taken together, these results indicate that Dab1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain.