RT Journal Article SR Electronic T1 Synergistic activation of RARβ and RARγ nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARα-controlled programs JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201627 DO 10.26508/lsa.202201627 VO 6 IS 2 A1 Aysis Koshy A1 Elodie Mathieux A1 François Stüder A1 Aude Bramoulle A1 Michele Lieb A1 Bruno Maria Colombo A1 Hinrich Gronemeyer A1 Marco Antonio Mendoza-Parra YR 2023 UL https://www.life-science-alliance.org/content/6/2/e202201627.abstract AB How cells respond to different external cues to develop along defined cell lineages to form complex tissues is a major question in systems biology. Here, we investigated the potential of retinoic acid receptor (RAR)–selective synthetic agonists to activate the gene regulatory programs driving cell specialization during nervous tissue formation from embryonic carcinoma (P19) and mouse embryonic (E14) stem cells. Specifically, we found that the synergistic activation of the RARβ and RARγ by selective ligands (BMS641 or BMS961) induces cell maturation to specialized neuronal subtypes, and to astrocytes and oligodendrocyte precursors. Using RAR isotype knockout lines exposed to RAR-specific agonists, interrogated by global transcriptome landscaping and in silico modeling of transcription regulatory signal propagation, revealed major RARα-driven gene programs essential for optimal neuronal cell specialization and hijacked by the synergistic activation of the RARβ and RARγ receptors. Overall, this study provides a systems biology view of the gene programs accounting for the previously observed redundancy between RARs, paving the way toward their potential use for directing cell specialization during nervous tissue formation.