Zhou Junxiang, Feng Chihin, Sun Yue, Noma Kentaro, Jin Yishi
Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093.
Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2025 Aug 26;122(34):e2507208122. doi: 10.1073/pnas.2507208122. Epub 2025 Aug 14.
The microtubule (MT) cytoskeleton is essential for neuronal morphology, neurite growth, synapse formation and maintenance, as well as regulation of signal transduction. Most cells express multiple isotypes of α- and β-tubulin that can coassemble into MTs. While a variety of signaling pathways regulate MT integrity and homeostasis, little is known about how tubulin isotypes interact in vivo. Here, we report a mechanism in which altered function of a neuronal β-tubulin in activates the conserved kinase DLK-1 and its downstream signal transduction, which in turn upregulates expression of an α-tubulin isotype to ensure MT integrity. We find that alteration in the T7 loop of the β-tubulin/BEN-1 causes the formation of BEN-1-enriched islands along MTs in neurites. Combining genome editing with cellular imaging, we identified amino acid residues in α-tubulin/TBA-2 that are necessary for formation of BEN-1 islands. Activation of DLK-1 signaling in mutants promotes TBA-2 transcription and protects axon and synapse morphology. These data uncover a positive feedback loop between DLK-1 and regulation of tubulin isotype interaction that maintains neuronal resilience.
微管（MT）细胞骨架对于神经元形态、神经突生长、突触形成与维持以及信号转导的调节至关重要。大多数细胞表达多种α-和β-微管蛋白同种型，它们可以共同组装成微管。虽然多种信号通路调节微管的完整性和稳态，但关于微管蛋白同种型在体内如何相互作用却知之甚少。在此，我们报告一种机制，即神经元β-微管蛋白功能的改变激活保守激酶DLK-1及其下游信号转导，进而上调一种α-微管蛋白同种型的表达以确保微管的完整性。我们发现β-微管蛋白/BEN-1的T7环改变会导致神经突中沿微管形成富含BEN-1的岛状物。将基因组编辑与细胞成像相结合，我们确定了α-微管蛋白/TBA-2中对于BEN-1岛状物形成所必需的氨基酸残基。突变体中DLK-1信号的激活促进TBA-2转录并保护轴突和突触形态。这些数据揭示了DLK-1与微管蛋白同种型相互作用调节之间的正反馈回路，该回路维持神经元的恢复力。
