and Other Unstable mRNAs The Wnt/-Catenin→Pitx2 Pathway Controls the Turnover of Pitx2 and Other Unstable mRNAs Molecular Cell, Vol. 12, 1201–1211, November, 2003.

Identification of a Wnt/Dvl/b-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development. Kioussi et al. Cell. 2002, 111(5):673-85

Baek et al. Proc Natl Acad Sci U S A. 2003, 100(6):3245-50 Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway. Baek et al. Proc Natl Acad Sci U S A. 2003, 100(6):3245-50 From previous report Rapid induction of Pitx2 by Wnt During development, tightly regulated expression of Pitx2 in time and space It might exist additional mechanism that regulates Pitx2 expression as well as TCF/LEF dependent manner Regulation of gene expression Transcriptional regulation Regulation of RNA stability

Rapid mRNA degradation requires three components Figure.1 Instability elements: ARE Trans-acting factors: ARE-BPs Enzyme: exosome

Altogether these data suggest that The expression of Pitx2 can be regulated at the level of its transcript turnover. Two regions, the CDS and the 3′UTR, contain destabilizing sequences. Pitx2 3′UTR displays class III ARE mediating exosome-dependent mRNA degradation

Figure.2 Altogether our findings suggest that the molecular target of Wnt signaling is the ARE-mediated decay of the mRNA. Wnt signaling regulates both transcriptional and mRNA turnover changes.

Figure.3 Specific interaction of ARE-BPs with Pitx2 3`-UTR in vitro. Changes in ARE-BPs interacted with Pitx2 RNA by Wnt signaling Wnt signaling induces changes in the nucleocytoplasmic distribution of ARE-BPs

Figure.5 Pitx2 plays a central role in the Wnt-activated regulatory pathway that stabilizes Pitx2, Cyclin D1, Cyclin D2, and c-Jun RNAs.

ARE-BPs subcellular localization Wnt b-catenin LEF/TCF ARE-BPs subcellular localization TTP-ARE KSRP-ARE HuR-ARE mRNA stabilization C-Jun Cyclin D1 Pitx2 CyclinD2