The Nesprin family member ANC-1 regulates synapse formation and axon termination by functioning in a pathway with RPM-1 and β-Catenin.
The Nesprin family member ANC-1 regulates synapse formation and axon termination by functioning in a pathway with RPM-1 and β-Catenin.
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DOI：
10.1371/journal.pgen.1004481
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发表时间：
2014-07
期刊：
影响因子：
4.5
通讯作者：
Grill B
中科院分区：
文献类型：
--
作者：
Tulgren ED;Turgeon SM;Opperman KJ;Grill B
Nesprin-1 和 2（也称为 Syne-1 和 2）的突变与许多疾病有关，包括自闭症、小脑性共济失调、癌症和 Emery-Dreifuss 肌营养不良症。 Nesprin-1 和 2 在果蝇和蠕虫中具有保守的直向同源物，分别称为 MSP-300 和异常核锚定 1 (ANC-1)。 Nesprin 蛋白家族介导细胞核和细胞器的锚定和定位。在神经系统中，Nesprin-1 和 2 唯一已知的功能是调节神经发生和神经迁移。目前尚不清楚 Nesprin-1 和 2 是否调节神经元中的其他功能。使用在线虫中的蛋白质组学方法，我们发现 ANC-1 与突触前形态调节因子 1 (RPM-1) 结合。 RPM-1 是称为 Pam/Highwire/RPM-1 (PHR) 蛋白的保守信号分子家族的一部分，是神经元发育的重要调节因子。我们发现 ANC-1 与 RPM-1 一样，调节轴突终止和突触形成。我们的遗传分析表明，ANC-1 通过 β-连环蛋白 BAR-1 发挥作用，ANC-1/BAR-1 通路在 RPM-1 下游自主地发挥细胞功能，调节神经元发育。此外，ANC-1 与细胞核的结合是其在轴突终止和突触形成中发挥作用所必需的。我们确定了四种不同 Wnt（LIN-44、EGL-20、CWN-1 和 CWN-2）的不同作用，它们通过 BAR-1 发挥作用来调节轴突终止。我们的研究强调了 ANC-1 在神经元发育中新兴的广泛作用，并揭示了 RPM-1 发挥作用的新的、意想不到的机制。支持突触形成和轴突终止的分子机制对于形成功能性、完全连接的神经系统至关重要。 PHR 蛋白是神经元发育的重要调节因子，在轴突生长和终止以及突触形成中发挥作用。在这里，我们描述了一种新的、保守的途径的发现，该途径受到线虫 PHR 蛋白 RPM-1 的正向调节。该通路由 RPM-1、ANC-1（一种 Nesprin 家族蛋白）和 BAR-1（一种典型的 β-连环蛋白）组成。 Nesprins，例如 ANC-1，调节多核细胞中的核锚定和定位。我们现在表明，在神经元中，ANC-1 通过正向调节 BAR-1 来调节神经元发育。因此，Nesprins 是多功能蛋白质，通过 β-连环蛋白发挥作用来调节神经元发育，并将细胞核与肌动蛋白细胞骨架连接起来，以介导多核细胞中的核锚定和定位。
Mutations in Nesprin-1 and 2 (also called Syne-1 and 2) are associated with numerous diseases including autism, cerebellar ataxia, cancer, and Emery-Dreifuss muscular dystrophy. Nesprin-1 and 2 have conserved orthologs in flies and worms called MSP-300 and abnormal nuclear Anchorage 1 (ANC-1), respectively. The Nesprin protein family mediates nuclear and organelle anchorage and positioning. In the nervous system, the only known function of Nesprin-1 and 2 is in regulation of neurogenesis and neural migration. It remains unclear if Nesprin-1 and 2 regulate other functions in neurons. Using a proteomic approach in C. elegans, we have found that ANC-1 binds to the Regulator of Presynaptic Morphology 1 (RPM-1). RPM-1 is part of a conserved family of signaling molecules called Pam/Highwire/RPM-1 (PHR) proteins that are important regulators of neuronal development. We have found that ANC-1, like RPM-1, regulates axon termination and synapse formation. Our genetic analysis indicates that ANC-1 functions via the β-catenin BAR-1, and the ANC-1/BAR-1 pathway functions cell autonomously, downstream of RPM-1 to regulate neuronal development. Further, ANC-1 binding to the nucleus is required for its function in axon termination and synapse formation. We identify variable roles for four different Wnts (LIN-44, EGL-20, CWN-1 and CWN-2) that function through BAR-1 to regulate axon termination. Our study highlights an emerging, broad role for ANC-1 in neuronal development, and unveils a new and unexpected mechanism by which RPM-1 functions. The molecular mechanisms that underpin synapse formation and axon termination are central to forming a functional, fully connected nervous system. The PHR proteins are important regulators of neuronal development that function in axon outgrowth and termination, as well as synapse formation. Here we describe the discovery of a novel, conserved pathway that is positively regulated by the C. elegans PHR protein, RPM-1. This pathway is composed of RPM-1, ANC-1 (a Nesprin family protein), and BAR-1 (a canonical β-catenin). Nesprins, such as ANC-1, regulate nuclear anchorage and positioning in multinuclear cells. We now show that in neurons, ANC-1 regulates neuronal development by positively regulating BAR-1. Thus, Nesprins are multi-functional proteins that act through β-catenin to regulate neuronal development, and link the nucleus to the actin cytoskeleton in order to mediate nuclear anchorage and positioning in multi-nuclear cells.
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影响因子：
4.8
作者：
Apel, ED;Lewis, RM;Sanes, JR
通讯作者：
Sanes, JR
影响因子：
30.8
作者：
Gros-Louis, Francois;Dupre, Nicolas;Rouleau, Guy A.
通讯作者：
Rouleau, Guy A.
影响因子：
16.2
作者：
Bamji, SX;Shimazu, K;Reichardt, LF
通讯作者：
Reichardt, LF
DOI：
10.1126/science.1165527
发表时间：
2009-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hammarlund M;Nix P;Hauth L;Jorgensen EM;Bastiani M
通讯作者：
Bastiani M
影响因子：
10.5
作者：
Bloom, A. Joseph;Miller, Bradley R.;DiAntonio, Aaron
通讯作者：
DiAntonio, Aaron