Fate plasticity of interneuron specification

Neuronal subtype generation in the mammalian central nervous system is governed by competing genetic programs. The medial ganglionic eminence (MGE) produces two major cortical interneuron (IN) populations, somatostatin (Sst) and parvalbumin (Pvalb), which develop on different timelines. The extent to which external signals influence these identities remains unclear. Pvalb-positive INs are crucial for cortical circuit regulation but challenging to model in vitro. We grafted mouse MGE progenitors into diverse 2D and 3D co-culture systems, including mouse and human cortical, MGE, and thalamic models. Strikingly, only 3D human corticogenesis models promoted efficient, non-autonomous Pvalb differentiation, characterized by upregulation of Pvalb maturation markers, downregulation of Sst-specific markers, and the formation of perineuronal nets. Additionally, lineage-traced postmitotic Sst-positive INs upregulated Pvalb when grafted onto human cortical models. These findings reveal unexpected fate plasticity in MGE-derived INs, suggesting that their identities can be dynamically shaped by the environment.