LIF signaling regulates outer radial glial to interneuron fate during human cortical development
Madeline G. Andrews, Clara Siebert, Li Wang, Matthew L. White, Jayden Ross, Raúl G. E. Morales, Megan E. Donnay, Gradi Bamfonga, Tanzila Mukhtar, Arpana Arjun McKinney, Kaila Gemenes, Shaohui Wang, Qiuli Bi, Elizabeth E. Crouch, Neelroop Parikshak, Georgia Panagiotakos, Eric J. Huang, Aparna Bhaduri, Arnold R. Kriegstein
Abstract
Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.