YAP1 Increases Organ Size and Expands Undifferentiated Progenitor Cells

The mechanisms that regulate mammalian organ size are poorly understood. It is unclear whether the pathways that control organ size also impinge on stem/progenitor cells. A highly expressed gene in stem cells is YAP1 [1Ramalho-Santos M. Yoon S. Matsuzaki Y. Mulligan R.C. Melton D.A. “Stemness”: transcriptional profiling of embryonic and adult stem cells.Science. 2002; 298: 597-600Crossref PubMed Scopus (1388) Google Scholar], the ortholog of Drosophila Yorkie, a downstream component of the Hippo pathway [2Huang J. Wu S. Barrera J. Matthews K. Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP.Cell. 2005; 122: 421-434Abstract Full Text Full Text PDF PubMed Scopus (1179) Google Scholar]. Mutations in components of this pathway produce tissue overgrowth phenotypes in the fly whereas mammalian orthologs, like salvador [3Tapon N. Harvey K.F. Bell D.W. Wahrer D.C. Schiripo T.A. Haber D.A. Hariharan I.K. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.Cell. 2002; 110: 467-478Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar], merlin [4McClatchey A.I. Giovannini M. Membrane organization and tumorigenesis—the NF2 tumor suppressor Merlin.Genes Dev. 2005; 19: 2265-2277Crossref PubMed Scopus (198) Google Scholar], LATS [5St John M.A. Tao W. Fei X. Fukumoto R. Carcangiu M.L. Brownstein D.G. Parlow A.F. McGrath J. Xu T. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction.Nat. Genet. 1999; 21: 182-186Crossref PubMed Scopus (349) Google Scholar], and YAP1 [6Overholtzer M. Zhang J. Smolen G.A. Muir B. Li W. Sgroi D.C. Deng C.X. Brugge J.S. Haber D.A. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.Proc. Natl. Acad. Sci. USA. 2006; 103: 12405-12410Crossref PubMed Scopus (681) Google Scholar, 7Zender L. Spector M.S. Xue W. Flemming P. Cordon-Cardo C. Silke J. Fan S.T. Luk J.M. Wigler M. Hannon G.J. et al.Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.Cell. 2006; 125: 1253-1267Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar], have been implicated in tumorigenesis. We report here that YAP1 increases organ size and causes aberrant tissue expansion in mice. YAP1 activation reversibly increases liver size more than 4-fold. In the intestine, expression of endogenous YAP1 is restricted to the progenitor/stem cell compartment, and activation of YAP1 expands multipotent undifferentiated progenitor cells, which differentiate upon cessation of YAP1 expression. YAP1 stimulates Notch signaling, and administration of γ-secretase inhibitors suppressed the intestinal dysplasia caused by YAP1. Human colorectal cancers expressing higher levels of YAP1 share molecular aspects with YAP1-induced dysplastic growth in the mouse. Our data show that the Hippo signaling pathway regulates organ size in mammals and can act on stem cell compartments, indicating a potential link between stem/progenitor cells, organ size, and cancer.