Developmental defects in Huntington’s disease show that axonal growth and microtubule reorganization require NUMA1

• Published in: Neuron (Cambridge, Mass.) Mass.), 2022-01, Vol.110 (1), p.36-50.e5
• Main Authors: Capizzi, Mariacristina, Carpentier, Rémi, Denarier, Eric, Adrait, Annie, Kassem, Rayane, Mapelli, Marina, Couté, Yohann, Humbert, Sandrine
• Format: Article
• Language: English
• Subjects: Animals; axonal growth; Axons - metabolism; Cell Cycle Proteins - metabolism; Growth Cones - physiology; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington’s disease; Mice; microtubule bundling; Microtubules - metabolism; neurodevelopment; nuclear/mitotic apparatus protein 1 (NUMA1); Proteomics
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.10.033

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. [Display omitted] •Huntington’s disease (HD) causes axonal growth defects during development•NUMA1 downregulation in HD leads to microtubule disorganization in the growth cone•NUMA1 downregulation phenocopies HD-induced axonal growth defects•Restoring NUMA1 expression rescues axonal growth in vivo Capizzi et al. show that Huntington’s disease (HD) limits axonal growth during development. The microtubules in the axonal growth cones are disorganized in HD because of NUMA1 downregulation. Restoring NUMA1 levels rescues axonal growth in HD mice.