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Summary In vitro modelling of highly vulnerable nigral dopaminergic (DA) neuronal subtypes in Parkinson’s disease (PD), is necessary for studying disease mechanisms. Here, we optimized a new approach by expressing the pioneer neurogenic transcription factor, Achaete-scute-like 1 ( Ascl1 ), implicated in determining dopaminergic fate. Sequential small-molecule patterning of iPSCs into early floor plate mesencephalic progenitors, followed by inducible Ascl1 expression, rapidly differentiates midbrain DA neurons. Immunocytochemistry and transcriptomic analysis of these patterned Ascl1-driven DA neurons (PA-DANs) confirmed midbrain-lineage specificity. Importantly, we found an enrichment of DA subpopulations that corresponded to the adult human ventral SOX6-positive A9 DA subtypes vulnerable in PD. Furthermore, we combined these ventral A9-like PA-DANs with human iPSC-derived midbrain astrocytes and microglia in defined ratios to generate mature 3D A9-like assembled organoids that display characteristic spontaneous neuronal activity and electrical propagation along the axon. Our method efficiently generates a mature and functional A9-like DA neuronal platform to study PD. Highlights Sequential midbrain patterning and Ascl1 expression accelerates DA differentiation PA-DANs resemble human adult ventral A9-like DA subtypes vulnerable in PD 3D assembled organoids show mature identity of PA-DANs, iAstrocytes and iMicroglia PA-DANs matured in 3D organoids show neuronal network activity within weeks eTOC blurb In this study, Ullian and colleagues have developed a rapid method to differentiate dopaminergic neurons, using small molecules to generate early floor plate mesencephalic progenitors from human iPSCs and sequentially expressing a pioneer transcription factor, Ascl1, that accelerates uniform dopaminergic neurogenesis. Patterned Ascl1-driven dopaminergic neurons (PA-DANs) in 2D and 3D assembled organoids serve as a platform to study Parkinson’s disease Abstract Figure
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