Mapping the developmental profile of ventricular zone-derived neurons in the human cerebellum

• 成果类型: Article
• 署名作者: Erickson, Anders W.; Tan, Henry; Hendrikse, Liam D.; Millman, Jake; Thomson, Zachary; Golser, Joseph; Khan, Omar; He, Guanyi; Bach, Kathleen; Mishra, Arpit Suresh; Kopic, Janja; Krsnik, Zeljka; Encha- Razavi, Ferechte; Petrilli, Giulia; Guimiot, Fabien; Silvestri, Evelina; Aldinger, Kimberly A.; Taylor, Michael D.; Millen, Kathleen J.; Haldipur, Parthiv
• 署名单位: University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Seattle Children's Hospital; Benaroya Research Institute; University of Zagreb; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Robert-Debre - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Azienda Ospedaliera San Camillo-Forlanini; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Texas Children's Cancer Center; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13143
• DOI: 10.1073/pnas.2415425122
• 发表日期: 2025-04-18
• 关键词: gabaergic interneurons; cortical layers; purkinje-cells; brain-stem; phenotype; absence; cortex; common; fate; pool

摘要

The cerebellar ventricular zone (VZ) is the primary source of progenitors that generate cerebellar GABAergic neurons, including Purkinje cells (PCs) and interneurons (INs). This study provides detailed characterization of human cerebellar GABAergic neurogenesis using transcriptomic and histopathological analyses and reveals conserved and unique features compared to rodents. We show that the sequential progression of neurogenesis is conserved and occurs before 8 postconception weeks. Notably, PC differentiation occurs in the outer subventricular zone (SVZ), a region absent in the mouse cerebellum. Human PCs are generated during a compact two-week period before the onset of cerebral cortex histogenesis. A subset of human PCs retain proliferative marker expression weeks after leaving the VZ, another feature not observed in rodents. Human PC maturation is protracted with an extensive migration and reorganization throughout development with dendritic arborization developing in late gestation. We define a continuous transcriptional cascade of PC development from neuroepithelial cells to mature PCs. In contrast, while human interneuronal progenitors are born beginning in early fetal development, they exhibit an even more protracted differentiation across late gestation and into postnatal ages. These findings show dynamic developmental process for human cerebellar GABAergic neurons and underscore the importance of the embryonic environment, with early disruptions having potentially significant impacts.