Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons
Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons
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DOI：
10.1016/j.ydbio.2004.09.024
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发表时间：
2005-01-15
影响因子：
2.7
通讯作者：
Shen, J
中科院分区：
文献类型：
--
作者：
Wines-Samuelson, M;Handler, M;Shen, J
早老素-1（PS1）是家族性阿尔茨海默病的主要致病基因，在早期神经发育过程中调节神经元分化和Notch信号。为了研究PS1在出生后大脑神经元迁移和皮质分层中的作用，我们通过产生条件性敲除（cKO）小鼠，其中PS1失活仅限于神经祖细胞（NPC）和NPC衍生的神经元和神经胶质细胞，从而避免了PS1缺失小鼠的围产期致死性。BrdU出生日期分析显示，许多晚出生的神经元未能迁移到早出生的神经元之外，到达它们在浅层中的适当位置，而早出生的神经元的迁移基本上是正常的。晚生神经元的迁移缺陷与PS1 cKO小鼠中放射状胶质细胞的逐渐减少相一致。与PS1缺失小鼠中Cajal-Retzius（CR）神经元的过早丢失相反，PS1 cKO小鼠中CR神经元的生成和存活不受影响。此外，增殖脑膜细胞的数量，这已被证明是重要的CR神经元的生存，增加了PS1-null小鼠，但不是在PS1 cKO小鼠。这些研究结果表明，PS1在皮质分层和放射状神经胶质细胞的发展中的细胞自主作用，以及PS1在CR神经元存活中的非细胞自主作用。(C)2004年爱思唯尔公司All rights reserved.
Presenilin-1 (PS1), the major causative gene of familial Alzheimer disease, regulates neuronal differentiation and Notch signaling during early neural development. To investigate the role of PS1 in neuronal migration and cortical lamination of the postnatal brain, we circumvented the perinatal lethality of PS1-null mice by generating a conditional knockout (cKO) mouse in which PS1 inactivation is restricted to neural progenitor cells (NPCs) and NPC-derived neurons and glia. BrdU birthdating analysis revealed that many late-born neurons fail to migrate beyond the early-born neurons to arrive at their appropriate positions in the superficial layer, while the migration of the early-born neurons is largely normal. The migration defect of late-born neurons coincides with the progressive reduction of radial glia in PS1 cKO mice. In contrast to the premature loss of Cajal-Retzius (CR) neurons in PS1-null mice, generation and Survival of CR neurons are unaffected in PS1 cKO mice. Furthermore, the number of proliferating meningeal cells, which have been shown to be important for the survival of CR neurons, is increased in PS1-null mice but not in PS1 cKO mice. These findings show a cell-autonomous role for PS1 in cortical lamination and radial glial development, and a non-cell-autonomous role for PS1 in CR neuron survival. (C) 2004 Elsevier Inc. All rights reserved.