Modeling Down Syndrome Cortical Neurogenesis in Human Cerebral Organoids

Trisomy of human chromosome 21 (HSA21) results in Down syndrome (DS), which is the leading genetic cause of intellectual disability. Due to limited experimental tools that allow the examination of human corticogenesis, information about the molecular signals underlying aberrant cortical development in DS is scarce. To recapitulate the complexity of human cortical development in an accessible system, we utilized induced pluripotent stem cells (iPSCs) derived from DS patients and age-matched cognitively normal controls, and examined the temporal and spatial expression of key neurogenic regulators during the development of human cerebral organoids (hCOs). We show, for the first time, impairments in the expression of genes regulating cell proliferation, fate determination and neuronal differentiation, as well as defective temporal control and spatial patterning of the developing cortex. We show that these impairments are apparent as early as day 27 of hCO development, which corresponds to gestation week 8. Additionally, we show altered expression of key neurogenic signals located on chromosome 21. These findings suggest that triplicated HSA21 severely compromises the expression of proteins mastering corticogenesis, which leads to defective brain development at early stages of gestation. This study establishes a gene network underlying brain malformation in DS.