Accelerated Tempo of Cortical Neurogenesis in Down Syndrome

Down syndrome (DS), caused by trisomy 21 (TS21), is the most common genetic cause of intellectual disability^1,2. The neurological impacts of DS first manifest during prenatal development through reduced radial glia (RG) neural stem cell proliferation, reduced cortical volume and imbalanced cortical cell types^3-6. However, the developmental mechanisms underlying altered cortical neurogenesis in DS remain elusive. Here we show by high-throughput lineage tracing in organotypic culture that TS21 accelerates RG lineage progression, driving premature production of cortical inhibitory neurons (INs) and oligodendrocytes. Somatic lineage coupling connects dysregulated neurogenic tempo to altered cellular composition in the adult DS brain. Finally, lineage-resolved differential expression reveals elevated interferon responses specifically in RG biased to producing INs. Together, our findings link TS21 genomic abnormalities to candidate molecular pathways and developmental mechanisms altering the cellular landscape in DS with therapeutic relevance.