RT Journal Article
SR Electronic
T1 Computational Identification of Ligand-Receptor Pairs that Drive Human Astrocyte Development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.31.491513
DO 10.1101/2022.05.31.491513
A1 AJ Voss
A1 SN Lanjewar
A1 MM Sampson
A1 A King
A1 E Hill
A1 A Sing
A1 C Sojka
A1 SA Sloan
YR 2022
UL http://biorxiv.org/content/early/2022/05/31/2022.05.31.491513.abstract
AB 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.HIGHLIGHTSComputational prediction of active ligand-receptor pairs in the developing brainSynergistic contributions of predicted ligands drive astrocyte developmentLigands induce transcriptomic and morphological features of mature astrocytesCooperative ligand activity converges on AKT/mTOR signalingCompeting Interest StatementThe authors have declared no competing interest.