Progenitor Diversity and Architecture of the Human Ganglionic Eminences Shaping the Basal Ganglia

Clara Siebert; Mengyi Song; Juan Moriano; Zhenmeiyu Li; Arantxa Cebrián‐Silla; Miranda Walker; Songcang Chen; Jennifer Baltazar; Lílian Gomes de Oliveira; Merut Shankar; Yuhan Xie; Pranav Varma Suraparaju; Shaohui Wang; Qiuli Bi; Yajun Xie; Yuqi Ren; Miguel Turrero Garcίa; Li Wang; Guolong Zuo; Marten P. Smidt; Marco F.M. Hoekman; Corey C. Harwell; Jack M. Parent; John L.R. Rubenstein; Arturo Álvarez-Buylla; Arnold R. Kriegstein

doi:10.64898/2025.12.31.697063

NeurosciencebioRxivJan 2, 2026

Preprint

Progenitor Diversity and Architecture of the Human Ganglionic Eminences Shaping the Basal Ganglia

Clara Siebert iD, Mengyi Song iD, Juan Moriano iD, Zhenmeiyu Li iD, Arantxa Cebrián‐Silla iD, Miranda Walker iD, Songcang Chen iD, Jennifer Baltazar iD, Lílian Gomes de Oliveira, Merut Shankar, Yuhan Xie, Pranav Varma Suraparaju iD, Shaohui Wang iD, Qiuli Bi, Yajun Xie iD, Yuqi Ren, Miguel Turrero Garcίa iD, Li Wang iD, Guolong Zuo iD, Marten P. Smidt iD, Marco F.M. Hoekman, Corey C. Harwell iD, Jack M. Parent iD, John L.R. Rubenstein iD, Arturo Álvarez-Buylla iD, Arnold R. Kriegstein iD

Abstract

The embryonic medial and lateral ganglionic eminences (MGE, LGE) are the principal sources of most neurons and glia for the basal ganglia. In primates, the MGE has a distinctive cytoarchitecture characterized by doublecortin enriched cellular nests (DENs), yet the architectonic organization underlying DEN formation, the molecular heterogeneity of ganglionic eminence progenitors and their lineage relationships, remain poorly understood. Here, using paired single-nucleus transcriptomics and chromatin accessibility profiling of the three GEs, we identify distinct progenitor populations, delineate their gene regulatory networks, and reconstruct their lineage trajectories. Live imaging reveals a unipolar outer radial glia-like population (GE-oRG) that undergoes mitotic somal translocation. Spatial transcriptomics identifies a distinct CRABP1+/ANGPT2+ domain within the MGE. Integrated spatial and electron microscopy demonstrates a periphery-to-center gradient of differentiation in the MGE. Leveraging DEN-forming MGE organoids derived from PCDH19 knockout human pluripotent stem cell lines, we identify the protocadherin, PCDH19, as a key regulator of DEN formation.

PDF DOI