Tgm2/Gh, Gbx1 and TGF-β are involved in retinoic acid-induced transdifferentiation from epidermis to mucosal epithelium

Abstract

We previouslydemonstrated that retinoic acid (RA)induces epidermis to transdifferen-WWe previouslyy ((RA)) transdifferentiate to mucosal epithelium with goblet cells in chick embryyonic cultured skin. To characterize the molecular mechanism of this transdifferentiation process, we used rat embryyonic cultured skin and immunohistochemistryy to confirm that RA-induced epidermal transdifferentiation accompanies the expression of markers of esophagus epithelium. Because Gbx1, TG2/Gh transglutaminase2)) and TGF-β2 are reported individuallyy to be induced byy RA in cultures of chick embryyonic skin, mouse epidermal cells and human hair follicles respectivelyy, here, we investigated whether cooperative interplayy of Gbx1, TG2/Gh and TGF-β2 is required for the transdifferentiation of epidermal cells to mucosal cells. We 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-β was expressed in the dermis. Inhibitors of the TGF-b signal pathwayy partiallyy inhibited transdifferentiation. Overexpression of both hTG2/Gh and mGbx1 together in the epidermis byy electroporation resulted in cuboidal cells in the upper cell layyers of the epidermis without keratinized layyers, although epidermal keratinization was observed in skin byy overexpression of either of them. Labeling DNA with BrdU indicated that RA directlyy transdifferentiated transient amplifyying epidermal cells, not stem cells, to mucosal cells. This studyy showed that coexpression of TG/2 and Gbx1 in the epidermis was required for esophagus-like mucosal transdifferentiation, and that increase in TGF-β2 expression byy RA in the dermis was essential to induce transdifferentiation through epithelial-mesenchyymal interaction. © 2011 UBC Press.