Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2302801120. doi: 10.1073/pnas.2302801120. Epub 2023 Sep 18.
Primary cilia are specialized organelles supporting the development and function of cells and organisms. Intraflagellar transport (IFT) is essential for cilia formation, maintenance, and function. In ciliated sensory neurons, IFT interacts with signaling molecules to generate distinct morphological and function features and also to maintain the integrity of cilia. Here, we report an IFT-dependent feedback control on the conserved MAPKKK DLK-1 in the ciliated sensory neurons. DLK proteins are widely known to act in synapse formation, axon regeneration, and degeneration, but their roles in other neuronal compartments are understudied. By forward genetic screening for altered expression of the endogenously tagged DLK-1 we identified multiple mutants showing increased DLK-1 accumulation in the defective sensory endings. We show that in response to acute IFT disruption, DLK-1 accumulates rapidly and reversibly. The expression levels of the transcription factor CEBP-1, known to act downstream of DLK-1 in the development and maintenance of synapses and axons, are also increased in the ciliated sensory neurons of mutants. Interestingly, the regulation of CEBP-1 expression shows sensory neuron-type dependency on DLK-1. Moreover, in the sensory neuron AWC, which has elaborate cilia morphology, up-regulated CEBP-1 represses DLK-1 at the transcription level, thereby dampening DLK-1 accumulation. Last, the IFT-dependent regulatory loop of DLK-1 and CEBP-1 offers neuroprotection in a cilia degeneration model. These findings uncover a surveillance mechanism in which tight control on the DLK-1 signaling protects cilia integrity in a context-specific manner.
纤毛是支持细胞和生物体发育和功能的特化细胞器。鞭毛内运输（IFT）对于纤毛的形成、维持和功能至关重要。在有纤毛的感觉神经元中，IFT 与信号分子相互作用，产生不同的形态和功能特征，并维持纤毛的完整性。在这里，我们报告了 IFT 对纤毛感觉神经元中保守的 MAPKKK DLK-1 的依赖性反馈控制。DLK 蛋白广泛参与突触形成、轴突再生和退化，但它们在其他神经元区室中的作用尚未得到充分研究。通过正向遗传筛选，我们发现了多个突变体，这些突变体表现出内源性标记的 DLK-1 表达增加，在有缺陷的感觉末端。我们表明，在急性 IFT 中断后，DLK-1 迅速且可逆地积累。已知在突触和轴突的发育和维持中充当 DLK-1 下游的转录因子 CEBP-1 的表达水平也在 突变体的纤毛感觉神经元中增加。有趣的是，CEBP-1 表达的调节表现出对 DLK-1 的感觉神经元类型依赖性。此外，在具有精细纤毛形态的感觉神经元 AWC 中，上调的 CEBP-1 在转录水平上抑制 DLK-1，从而抑制 DLK-1 的积累。最后，DLK-1 和 CEBP-1 的 IFT 依赖性调节环在纤毛退化模型中提供神经保护。这些发现揭示了一种监控机制，其中对 DLK-1 信号的严格控制以特定于上下文的方式保护纤毛的完整性。
