Regional diversity of outer radial glia Characterization of a novel oRG-like progenitor in the human developing ganglionic eminences

Outer radial glia(oRG) cells are a key progenitor population in the developing cortex, believedto facilitate cortical expansion during midgestation. Several studies havehinted at the presence of oRG cells in the human ganglionic eminences (GEs),the ventral forebrain regions where inhibitory interneurons are produced, butthis has not been thoroughly investigated. Using live imaging ofGW13-19 primary medial (MGE), lateral (LGE), and caudal (CGE) GEs, we identifya novel GE progenitor subtype that resembles cortical oRG and that we termGE-oRG. It is characterized by mitotic somal translocation (MST) behaviorduring division and morphology of a single dominant process. MST divisions predominateat GW13-14 and decline at GW17-19, particularly in the MGE. Usingsingle-cell/ATAC sequencing (multiome) and spatial transcriptomics, we definethe molecular profile of GE-oRG cells, that localize to the oSVZ in MGE and LGE(GW23), and propose PTPRZ1 and ATP1A2 as candidate co-markers.These markers will be validated in future experiments. We also explore MGEorganoids as an in vitro model to study MGE development and find that organoidscontain progenitor cells that exhibit MST, replicate major progenitor andinterneuron subclasses, and form DENs/type 1 and 2 progenitor clusters aspreviously described in human brain samples of developing tissue. Finally, weshow that cortical oRGs can give rise to CGE-like interneurons, furthersupporting the idea that oRGs may have broader developmental potential thanpreviously assumed. Altogether, this work provides new insight into regionaloRG diversity.