Progenitor expansion in apc mutants is mediated by Jak/Stat signaling

Here we show that stat3, a known oncogene and a target of ？-catenin in multiple tissues, is upregulated in apc mutant zebrafish embryos. We further demonstrate that Jak/Stat signaling is necessary for the increased level of proliferation and neural progenitor gene expression observed in apc mutants.Together, our data suggest that the regulation of Jak/Stat signaling may represent a conserved mechanism explaining the expansion of undifferentiated cells downstream of APC mutations.The Wnt/？-catenin signaling pathway acts to maintain the undifferentiated progenitor state in multiple epithelial tissues, and overactivation of this pathway is a major contributor to cancer. The tumor suppressor APC normally functions to inhibit Wnt/？-catenin signaling, and APC mutations are oncogenic in tissues such as the colorectal epithelium [1]. During normal embryonic development, Wnt and APC activities are balanced to allow both progenitor cell expansion and differentiation of postmitotic derivatives. Zebrafish embryos homozygous for apc mutations exhibit mispatterning and failure of differentiation in multiple tissues including the central nervous system (CNS) [2,3]. Furthermore, in the CNS of other vertebrates, loss of APC function specifically leads to arrest in the neural progenitor state [4]. Despite a clear picture of the cellular phenotypes following loss of APC, the molecular pathways underlying CNS progenitor cell expansion are largely unknown. These pathways may represent good candidates for mediators of oncogenesis in other epithelial cells.The main downstream output of Wnt/？-catenin signaling is the transcriptional regulation of target genes, mediated by Lef/Tcf family members. Typically, these targets are repressed by Lef/Tcf factors in the absence of Wnt signaling, and following Wnt activation ？-catenin translocates to the nucleus where it binds to Lef/Tcf proteins and acts as a co-activator. The identification of Wnt/？-catenin transcriptional targets has thus been a ma