biostudies-literatureNandagopal SNational Institutes of HealthNational Institute of General Medical SciencesDamon Runyon Cancer Research FoundationNIGMS NIH HHS115077https://www.ebi.ac.uk/biostudies/studies/S-EPMC11774475biostudies-literatureUnknown43(12)Stem cells integrate multiple environmental signals to activate appropriate fate programs. To ensure coherent responses, alternative fates must be concomitantly inactivated. However, mechanisms that coordinate fates in a signal-specific manner are not fully understood. Here, we investigate the role of a network of basic-helix-loop-helix (bHLH) transcription factors in neural stem cells, which integrate leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling to synergistically induce glial fibrillary acidic protein (GFAP), a key astrocyte-fate determinant. Using quantitative RNA-fluorescence in situ hybridization (FISH) and ectopic expression, we find that multiple bHLHs that promote alternative fates also repress GFAP but are all suppressed by BMP and, to a lesser eCell reportsActivation-derepression synergy enables a bHLH network to coordinate a signal-specific fate response.PMC11774475K99 GM151398DRG-2339-18R35 GM1395721K99GM151398Terrio AVicente FZLahav GNandagopal SMegason SGJambhekar AfalseActivation-derepression synergy enables a bHLH network to coordinate a signal-specific fate response.Stem cells integrate multiple environmental signals to activate appropriate fate programs. To ensure coherent responses, alternative fates must be concomitantly inactivated. However, mechanisms that coordinate fates in a signal-specific manner are not fully understood. Here, we investigate the role of a network of basic-helix-loop-helix (bHLH) transcription factors in neural stem cells, which integrate leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling to synergistically induce glial fibrillary acidic protein (GFAP), a key astrocyte-fate determinant. Using quantitative RNA-fluorescence in situ hybridization (FISH) and ectopic expression, we find that multiple bHLHs that promote alternative fates also repress GFAP but are all suppressed by BMP and, to a lesser e2024-01-01T00:00:00Z2024 Dec2026-05-29T14:18:18.842Z2025-04-04T22:24:31.118ZS-EPMC117744753967128710.1016/j.celrep.2024.115077