Retinoid and serotonergic signaling at sites of epithelial-mesenchymal interaction

This study focuses on the apparent relationship between the serotonin 2B (5-HT_2B) receptor and retinoid signaling pathways. In order to reconcile the similarities of craniofacial defects seen in embryos teratogenized by retinoic acid (RA) and 5-HT₂ receptor antagonism, the role of each signaling pathway on patterning and non-patterning events in the frontonasal mass (FNM) was examined. This study shows that these signals require epithelial-mesenchymal (E-M) interactions for proper expression and function. The apparent relationships between retinoid signaling and fibroblast growth factor 8 (Fgf8), sonic hedgehog (shh), bone morphogenetic protein 4 (Bmp4) and the 5-HT_2B receptor led us to ask whether RA exerts its effects on morphogenesis and differentiation by transcriptionally regulating these potential targets. In vitro systems were utilized to pharmocologically manipulate these signaling pathways to determine their affects on morphogenetic processes, including patterning, cell proliferation and chondrogenesis. Results indicate that RA treatment and activation of the 5-HT_2B receptor lead to opposing effects on cell proliferation in the FNM and on chondrogenesis in the hindlimb. This study provides further insights into the relationships between the action of RA and the 5-HT_2B receptor at sites of E-M interaction.