�e previousl� demonstrated that retinoic acid �RA� induces epidermis to transdifferen�e previousl� demonstrated that retinoic acid �RA� induces epidermis to transdifferentiate to mucosal epithelium with goblet cells in chick embr�onic cultured skin. To characterize the molecular mechanism of this transdifferentiation process, we used rat embr�onic cultured skin and immunohistochemistr� to confirm that RA-induced epidermal transdifferentiation accompanies the expression of markers of esophagus epithelium. Because Gbx1, TG2/Gh �transglutaminase2� and TGF-b2 are reported individuall� to be induced b� RA in cultures of chick embr�onic skin, mouse epidermal cells and human hair follicles respectivel�, here, we investigated whether cooperative interpla� of Gbx1, TG2/Gh and TGF-b2 is required for the transdifferentiation of epidermal cells to mucosal cells. �e have shown that expression of Gbx1, TG2/Gh and TGF-b proteins were all upregulated in RA-induced transdifferentiated skin and that the former two were expressed in the epidermis, while TGF-b was expressed in the dermis. Inhibitors of the TGF-b signal pathwa� partiall� inhibited transdifferentiation. Overexpression of both hTG2/Gh and mGbx1 together in the epidermis b� electroporation resulted in cuboidal cells in the upper cell la�ers of the epidermis without keratinized la�ers, although epidermal keratinization was observed in skin b� overexpression of either of them. Labeling DNA with BrdU indicated that RA directl� transdifferentiated transient amplif�ing epidermal cells, not stem cells, to mucosal cells. This stud� showed that coexpression of TG/2 and Gbx1 in the epidermis was required for esophagus-like mucosal transdifferentiation, and that increase in TGF-b2 expression b� RA in the dermis was essential to induce transdifferentiation through epithelial-mesench�mal interaction.