Although the classic symptoms of Huntington’s disease (HD) manifest in adulthood, neural progenitor cell behavior is already abnormal by 13 weeks’ gestation. To determine how these developmental defects evolve, we turned to cell and mouse models. We found that layer II/III neurons that normally connect the hemispheres are limited in their growth in HD by microtubule bundling defects within the axonal growth cone, so that fewer axons cross the corpus callosum. Proteomic analyses of the growth cones revealed that NUMA1 (nuclear/mitotic apparatus protein 1) is downregulated in HD by miR-124. Suppressing NUMA1 in wild-type cells recapitulates the microtubule and axonal growth defects of HD, whereas raising NUMA1 levels with antagomiR-124 or stabilizing microtubules with epothilone B restores microtubule organization and rescues axonal growth. NUMA1 therefore regulates the microtubule network in the growth cone, and HD, which is traditionally conceived as a disease of intracellular trafficking, also disturbs the cytoskeletal network.

尽管亨廷顿氏病 (HD) 的典型症状在成年期出现，但到妊娠 13 周时，神经祖细胞行为已经异常。为了确定这些发育缺陷是如何演变的，我们求助于细胞和小鼠模型。我们发现，通常连接半球的 II/III 层神经元在 HD 中的生长受限于轴突生长锥内的微管束缺陷，因此更少的轴突穿过胼胝体。生长锥的蛋白质组学分析显示 NUMA1（核/有丝分裂器蛋白 1）在 HD 中被 miR-124 下调。抑制野生型细胞中的 NUMA1 可概括 HD 的微管和轴突生长缺陷，而用 antagomiR-124 提高 NUMA1 水平或用埃博霉素 B 稳定微管可恢复微管组织并挽救轴突生长。