Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655.
Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1358-1363. doi: 10.1073/pnas.1715837115. Epub 2018 Jan 2.
Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the CH zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with mutants, linking to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.
Wallerian 变性的遗传研究已经确定了一些信号分子（例如 dSarm/Sarm1、Axundead 和 Highwire），它们在轴突中局部发挥作用以驱动变性。在这里，我们确定了 CH 锌指转录因子 Pebbled[Peb，哺乳动物中的 Ras 反应元件结合蛋白 1（RREB1）]在轴突死亡中的作用。谷氨酸能感觉神经元中 Peb 的缺失导致切断的轴突完全保留，或者轴突死亡表型，其中轴突断裂成大的连续片段，而不是完全解体。Peb 在发育中和成熟的感觉神经元中表达，表明它需要建立或维持它们发生轴突死亡的能力。突变表型可以被人类 RREB1 拯救，并且它们与突变体表现出显性遗传相互作用，将与轴突死亡信号级联联系起来。令人惊讶的是，Peb 仅能够完全阻断谷氨酸能但不能阻断胆碱能感觉神经元中的轴突死亡信号转导，这表明不同神经元亚型的轴突死亡信号转导程序存在遗传多样性。我们的发现确定了一种调节轴突死亡信号转导的转录因子，并且突变体的部分片段化表型揭示了轴突死亡信号转导中的一个遗传上可接近的步骤。
