YAP1 Increases Organ Size and Expands Undifferentiated Progenitor Cells

• Published in: Current biology Vol. 17; no. 23; pp. 2054 - 2060
• Main Authors: Camargo, Fernando D., Gokhale, Sumita, Johnnidis, Jonathan B., Fu, Dongdong, Bell, George W., Jaenisch, Rudolf, Brummelkamp, Thijn R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 04.12.2007
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenoma - metabolism; Animals; Cell Differentiation; Cell Proliferation; CELLBIO; CELLCYCLE; Colorectal Neoplasms - metabolism; Humans; Intestine, Small - cytology; Intestine, Small - metabolism; Liver - anatomy & histology; Liver - cytology; Liver - metabolism; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Organ Size; Phosphoproteins - genetics; Phosphoproteins - metabolism; Signal Transduction; Stem Cells - cytology; Transcription Factors; CELLBIO; CELLCYCLE
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2007.10.039

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[1], the ortholog of Drosophila Yorkie, a downstream component of the Hippo pathway [2]. Mutations in components of this pathway produce tissue overgrowth phenotypes in the fly whereas mammalian orthologs, like salvador [3], merlin [4], LATS[5], and YAP1[6, 7], 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.