Understanding and modeling regional specification of the human ganglionic eminence

Inhibitory neurons originating from the ventral forebrain are associated with several neurological conditions. Distinct ventral forebrain subpopulations are generated from topographically defined zones; lateral-, medial- and caudal ganglionic eminences (LGE, MGE and CGE), yet key specification factors often span across developing zones contributing to difficulty in defining unique LGE, MGE or CGE profiles. Here we use human pluripotent stem cell (hPSC) reporter lines (NKX2.1-GFP and MEIS2-mCherry) and manipulation of morphogen gradients to gain greater insight into regional specification of these distinct zones. We identified Sonic hedgehog (SHH)-WNT crosstalk in regulating LGE and MGE fate and uncovered a role for retinoic acid signaling in CGE development. Unraveling the influence of these signaling pathways permitted development of fully defined protocols that favored generation of the three GE domains. These findings provide insight into the context-dependent role of morphogens in human GE specification and are of value for in vitro disease modeling and advancement of new therapies. •What specifies the human ganglionic eminences (GE) remains poorly understood•Controlled morphogen delivery to human stem cells separates GE subpopulations•GE subpopulations could be enriched via cell sorting using reporter stem cell lines•Transplanted progenitors generated appropriate mature inhibitory neuron populations Parish and colleagues use pluripotent stem cells to model specification of neighboring, yet functionally distinct, inhibitory neuron subpopulations of the human ganglionic eminences (GE). Fine-tuning morphogen delivery drove GE regional specification, with enrichment via cell sorting using novel reporter cell lines. Transplanted progenitors generated mature inhibitory neurons. Findings are important for understanding development, modeling neurological disorders, and advancing therapies.