Survival of developing motor neurons mediated by Rho GTPase signaling pathway through Rho-kinase
Survival of developing motor neurons mediated by Rho GTPase signaling pathway through Rho-kinase
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DOI：
10.1523/jneurosci.0295-04.2004
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发表时间：
2004-04-07
影响因子：
5.3
通讯作者：
Kobayashi, K
中科院分区：
文献类型：
--
作者：
Kobayashi, K;Takahashi, M;Kobayashi, K
胚胎发育过程中产生的各种神经元在发育后期存活或经历程序性细胞死亡（PCD）。通常认为发育中的神经元的存活或死亡取决于各种靶组织的营养支持。小 GTPaseRho 调节多种细胞过程，如细胞形态、细胞粘附、细胞运动和细胞凋亡。 Rho 依赖性丝氨酸-苏氨酸蛋白激酶 (Rho-kinase-ROK-ROCK) 是效应蛋白之一，为一些 Rho 介导的过程传递信号。在这里，我们报告了 Rho 信号通路在脊髓运动神经元 (MN) 发育过程中通过 Rho 激酶的体内作用。我们通过使用 Cre-loxP 系统在转基因小鼠中条件表达 RhoA (RhoADN) 或 Rho 激酶 (Rho-KDN) 的显性失活形式，以抑制发育中的 MN 中这些信号分子的活性。 RhoA DN 的表达减少了脊髓中 MN 的数量，因为细胞凋亡增加，同时保留了运动轴突的总体模式。 Rho-K DN 的表达产生了与 RhoA DN 表达中观察到的相似的发育缺陷。此外，对表达Rho-K DN的转基因小鼠的分析表明，在PCD开始之前的早期胚胎阶段诱导了MN细胞凋亡的增加，并且在转基因小鼠中，对应于PCD时期的胚胎晚期阶段MN的死亡适度增加。这些发现表明，Rho 信号通路（主要通过 Rho 激酶）在胚胎发生过程中脊髓 MN 的存活中发挥着至关重要的作用，特别是在早期发育阶段。
A variety of neurons generated during embryonic development survive or undergo programmed cell death (PCD) at later developmental stages. Survival or death of developing neurons is generally considered to depend on trophic support from various target tissues. The small GTPaseRho regulates diverse cellular processes such as cell morphology, cell adhesion, cell motility, and apoptosis. Rho-dependent serine-threonine protein kinase (Rho-kinase-ROK-ROCK), one of the effector proteins, transmits signals for some Rho-mediated processes. Here, we report the in vivo role of the Rho signaling pathway through Rho-kinase during development of motor neurons (MNs) in the spinal cord. We performed conditional expression of a dominant-negative form for RhoA(RhoADN) or for Rho-kinase (Rho-KDN) in transgenic mice by using the Cre-loxP system to suppress the activity of these signaling molecules in developing MNs. Expression of RhoA DN reduced the number of MNs in the spinal cord because of increased apoptosis while preserving the gross patterning of motor axons. Expression of Rho-K DN produced developmental defects similar to those observed in RhoA DN expression. In addition, analysis of transgenic mice expressing Rho-K DNshowed that the increased apoptosis of MNs was induced at the early embryonic stages before the initiation of PCD, and that MN death at the late embryonic stages corresponding to the period of PCD was moderately enhanced in the transgenic mice. These findings indicate that the Rho signaling pathway, primarily through Rho-kinase, plays a crucial role in survival of spinal MNs during embryogenesis, particularly at the early developmental stages.