10.1016/j.isci.2025.112295

iScience 2025

Mostajo-Radji, Mohammed A. and Leon, Walter R. Mancia and Breevoort, Arnar and Gonzalez-Ferrer, Jesus and Schweiger, Hunter E. and Lehrer, Julian and Zhou, Li and Schmitz, Matthew T. and Perez, Yonatan and Mukhtar, Tanzila and Robbins, Ash and Chu, Julia and Andrews, Madeline G. and Sullivan, Frederika N. and Tejera, Dario and Choy, Eric C. and Paredes, Mercedes F. and Teodorescu, Mircea and Kriegstein, Arnold R. and Alvarez-Buylla, Arturo and Pollen, Alex A.

Abstract

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.

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