UC San Diego

Down syndrome (DS), caused by the triplication of chromosome 21, results in various physical, intellectual, and neurodevelopmental abnormalities. Despite extensive research, the precise molecular mechanisms and pathways disrupted by trisomy 21 during brain development remain largely unknown due to the complexity of the disorder and the limitations of traditional research models. However, numerous studies point to specific defects in DS neural progenitor cells (NPCs), resulting in aberrant brain development. This study examines the molecular and cellular consequences of trisomy 21 (T21) using induced pluripotent stem cells (iPSCs) differentiated into neural progenitor cells (NPCs), neurons, astrocytes, and 3D brain organoids to model early neurodevelopmental processes and cell fate decisions. RNA sequencing and gene ontology (GO) analysis revealed a disruption in neuro- and glio-genesis as well as cell cycles in NPCs. By utilizing 3D brain organoids, I also identified altered cell cycle and cell fate specification as a consequence of T21. My findings highlight the vulnerability of NPCs to T21 and suggest that differentiation is disrupted by T21.