SUMMARY
Extrinsic signaling between diverse cell types is crucial to nervous system development. Ligand binding is a key driver of developmental processes, but it remains a significant challenge to disentangle how collections of these signals act cooperatively to affect changes in recipient cells. In the developing human brain, cortical progenitors transition from neurogenesis to gliogenesis in a stereotyped progression that is influenced by extrinsic ligands. Therefore, we sought to use the wealth of published genomic data in the developing human brain to identify and then test novel ligand combinations that act synergistically to drive gliogenesis. Using computational tools, we identified ligand-receptor pairs that are expressed at appropriate developmental stages, in relevant cell types, and whose activation is predicted to cooperatively stimulate complimentary astrocyte gene signatures. We then tested a group of five neuronally-secreted ligands and validated their synergistic contributions to astrocyte development within both human cortical organoids and primary fetal tissue. We confirm cooperative capabilities of these ligands far greater than their individual capacities and discovered that their combinatorial effects converge on AKT/mTOR signaling to drive transcriptomic and morphological features of astrocyte development. This platform provides a powerful agnostic framework to identify and test how extrinsic signals work in concert to drive developmental processes.
HIGHLIGHTS
Computational prediction of active ligand-receptor pairs in the developing brain
Synergistic contributions of predicted ligands drive astrocyte development
Ligands induce transcriptomic and morphological features of mature astrocytes
Cooperative ligand activity converges on AKT/mTOR signaling
Competing Interest Statement
The authors have declared no competing interest.
