PT  - JOURNAL ARTICLE
AU  - Aysis Koshy
AU  - Elodie Mathieux
AU  - François Stüder
AU  - Aude Bramoulle
AU  - Michele Lieb
AU  - Bruno Maria Colombo
AU  - Hinrich Gronemeyer
AU  - Marco Antonio Mendoza-Parra
TI  - Synergistic activation of RARβ and RARγ nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARα-controlled programs
AID  - 10.26508/lsa.202201627
DP  - 2023 Feb 01
TA  - Life Science Alliance
PG  - e202201627
VI  - 6
IP  - 2
4099  - https://www.life-science-alliance.org/content/6/2/e202201627.short
4100  - https://www.life-science-alliance.org/content/6/2/e202201627.full
SO  - Life Sci. Alliance2023 Feb 01; 6
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.