Negative Interplay of Retinoic Acid and TGF-β Signaling Mediated by TG-Interacting Factor to Modulate Mouse Embryonic Palate Mesenchymal-Cell Proliferation

Mesenchymal-cell proliferation is the main process in shelf outgrowth. Both all-trans-retinoic acid (atRA) and transforming growth factor-3 (TGF-3) play an important role in mouse embryonic palate mesenchymal (MEPM) cell proliferation. In the present study, we investigated the crosstalk between RA and TGF- signaling in MEPM-cell proliferation. We found that atRA inhibited MEPM-cell proliferation by downregulating TGF-/Smad signaling and that TGF-3 treatment was able to antagonize RA signaling. Transforming growth-interacting factor (TGIF) is a transcriptional repressor that suppresses both TGF-- and retinoid-driven gene transcription. Furthermore, we investigated the role of TGIF in the interaction between both TGF- and RA signaling in MEPM-cell proliferation. The results showed that both atRA and TGF-3 significantly increased the expression level of TGIF, and TGIF mediated the negative interaction between TGF- and RA signaling pathways, which depended on TGIF binding to Smad2 or RAR (RA receptor beta). Moreover, after deletion of TGIF, both the effects of atRA on TGF--dependent protein expression and the effects of TGF- on RA-dependent protein expression were lost. So we conclude that there is a negative functional interplay of RA and TGF- signaling mediated by TGIF to modulate MEPM-cell proliferation (C) 2014 Wiley Periodicals, Inc.