The Wnt/-Catenin→Pitx2 Pathway Controlsthe Turnover of Pitx2

and Other Unstable mRNAs

Molecular Cell, Vol. 12, 1201–1211, November, 2003.

Identification of a Wnt/Dvl/-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development.

Kioussi et al. Cell. 2002, 111(5):673-85

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 WntDuring 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: ARETrans-acting factors: ARE-BPsEnzyme: 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 isthe ARE-mediated decay of the mRNA.

Wnt signaling regulates both transcriptional and mRNA turnover changes.

Figure.3A. 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.

Wnt

-catenin

LEF/TCF

Pitx2C-Jun Cyclin D1

CyclinD2

ARE-BPs subcellular localization

TTP-AREKSRP-AREHuR-ARE

mRNA stabilization