In the central nervous system (CNS), neurons need synaptic neurotransmitter release and cellular response for various cellular stress or environmental stimuli. To achieve these highly orchestrated cellular processes, neurons should drive the molecular mechanisms that govern and integrate complex signaling pathways. The signal transduction ATPases with numerous domains (STAND) family of proteins has been shown to play essential roles in diverse signal transduction mechanisms, including apoptosis and innate immunity. However, a comprehensive understanding of STAND genes remains lacking. Previously, we identified the NACHT and WD repeat domain-containing protein 1 (NWD1), a member of STAND family, in the regulation of the assembly of a giant multi-enzyme complex that enables efficient de novo purine biosynthesis during brain development. Here we identified the mouse Nwd2 gene, which is a paralog of Nwd1. A molecular phylogenetic analysis suggested that Nwd1 emerged during the early evolution of the animal kingdom, and that Nwd2 diverged in the process of Nwd1 duplication. RT-PCR and in situ hybridization analyses revealed the unique expression profile of Nwd2 in the developing and adult CNS. Unlike Nwd1, Nwd2 expression was primarily confined to neurons in the medial habenular nucleus, an essential modulating center for diverse psychological states, such as fear, anxiety, and drug addiction. In the adult brain, Nwd2 expression, albeit at a lower level, was also observed in some neuronal populations in the piriform cortex, hippocampus, and substantia nigra pars compacta. NWD2 might play a unique role in the signal transduction required for specific neuronal circuits, especially for cholinergic neurons in the habenula.

在中枢神经系统 (CNS) 中，神经元需要突触神经递质释放和细胞对各种细胞应激或环境刺激的反应。为了实现这些高度协调的细胞过程，神经元应该驱动控制和整合复杂信号通路的分子机制。具有众多结构域的信号转导 ATP 酶 (STAND) 蛋白家族已被证明在多种信号转导机制中发挥重要作用，包括细胞凋亡和先天免疫。然而，仍然缺乏对 STAND 基因的全面了解。以前，我们发现了 NACHT 和 WD 重复结构域蛋白 1 (NWD1)，它是 STAND 家族的一员，在调控巨型多酶复合物的组装过程中能够有效地从头开始大脑发育过程中的嘌呤生物合成。在这里，我们确定了小鼠Nwd2基因，它是Nwd1的旁系同源基因。分子系统发育分析表明，Nwd1在动物界的早期进化过程中出现，而Nwd2在Nwd1复制过程中分化。RT-PCR 和原位杂交分析揭示了Nwd2在发育中和成人中枢神经系统中的独特表达谱。与Nwd1不同，Nwd2表达主要局限于内侧缰核中的神经元，内侧缰核是恐惧、焦虑和毒瘾等多种心理状态的重要调节中心。在成人大脑中，在梨状皮质、海马体和黑质致密部的一些神经元群中也观察到Nwd2表达，尽管水平较低。NWD2 可能在特定神经回路所需的信号转导中发挥独特作用，尤其是缰核中的胆碱能神经元。