Mechanisms and Regulation of Transforming Growth Factor Superfamily Mediated Gene Expression.

The TGF-beta superfamily, including TGF-betas and BMPs, is critical for normal embryonic development, as well as disease progression, and is tightly regulated both within and out of cells. In vitro, TGF-beta signaling mediated epithelial-mesenchymal transition (EMT) by activating mesenchymal genes and suppressing epithelial markers. We discovered that Wnt11 was directly regulated by the mediators of TGF-beta signaling, Smad proteins. The induction of Wnt11 expression was critical for TGF-beta associated activation of mesenchymal marker genes. Instead of modulating Smad proteins or activating canonical/beta-Catenin signaling, Wnt11 controlled mesenchymal gene activation through JNK signaling. Our findings, for the first time, demonstrated the cooperativity among the TGF-beta, Wnt11 and JNK signaling pathways in the context of EMT. Both TGF-beta and BMP signaling are involved in renal fibrosis, but with opposite functions. TGF-beta is a well known pro-fibrogenic factor, while BMP counteracts TGF-beta to protect kidney from injuries. In our study, transgenic expression of kielin/chordin-like protein (KCP), an inhibitor of TGF-beta and enhancer of BMP7, in renal epithelia attenuated the upregulation of mesenchymal genes in the injured kidney of unilateral ureteral obstruction (UUO) mouse model. These data demonstrated the importance of the balance of TGF-beta and BMP signaling in the progression of renal fibrosis and provided a new potential therapeutic target. During kidney development, both BMP7 and Tle4, a common corepressor, are present in metanepheric mesenchymal cells. However, their relationship is unknown. Here, we found that overexpression of Tle4 not only activated a BMP reporter, but also enhanced and sustained the upregulation of endogenous Id1 gene induced by BMP7. The effect of Tle4 on BMP signaling was through mediating Smad7 protein, for Tle4 repressed Smad7 expression and overexpression of Smad7 totally abolished the activation of the BMP reporter by Tle4. Our study provides a new potential mechanism for the regulation of BMP signaling in the kidney development.PHDMolecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96131/1/pzh_1.pd