Park Seungmee, Jin Yishi, Chisholm Andrew D
Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Genetics. 2025 Sep 3;231(1). doi: 10.1093/genetics/iyaf122.
Neurons maintain their morphology over prolonged periods of adult life with limited regenerative capacity. Among the various factors that shape neuronal morphology, lipids function as membrane components, signaling molecules, and regulators of synaptic plasticity. Here, we tested genes involved in phospholipid biosynthesis and identified their roles in axon regrowth and maintenance. CEPT-2 and EPT-1 are enzymes catalyzing the final steps in the de novo phospholipid synthesis (Kennedy) pathway. Loss of function mutants of cept-2 or ept-1 show reduced axon regrowth and failure to maintain axon morphology. We demonstrate that CEPT-2 is required cell-autonomously to prevent age-related axonal morphology defects. We further investigated genetic interactions of cept-2 or ept-1 with dip-2, a conserved regulator of lipid metabolism that affects axon morphology maintenance and regrowth after injury. Loss-of-function in dip-2 led to suppression of axon regrowth defects observed in either cept-2 or ept-2 mutants, suggesting that DIP-2 acts to counterbalance phospholipid synthesis. Our findings reveal the genetic regulation of lipid metabolism as critical for axon maintenance following injury and during aging.
神经元在成年后的很长一段时间内保持其形态，再生能力有限。在塑造神经元形态的各种因素中，脂质作为膜成分、信号分子和突触可塑性的调节剂发挥作用。在这里，我们测试了参与磷脂生物合成的基因，并确定了它们在轴突再生和维持中的作用。CEPT-2和EPT-1是催化从头合成磷脂（肯尼迪）途径最后步骤的酶。cept-2或ept-1的功能丧失突变体显示轴突再生减少且无法维持轴突形态。我们证明CEPT-2是细胞自主必需的，以防止与年龄相关的轴突形态缺陷。我们进一步研究了cept-2或ept-1与dip-2的遗传相互作用，dip-2是一种保守的脂质代谢调节剂，影响损伤后轴突形态的维持和再生。dip-2的功能丧失导致在cept-2或ept-2突变体中观察到的轴突再生缺陷受到抑制，这表明DIP-2起到平衡磷脂合成的作用。我们的研究结果揭示了脂质代谢的遗传调控对于损伤后和衰老过程中的轴突维持至关重要。
