c Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues. Yap deficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5) Yap conditional knockout and YAP transgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR and in situ hybridization. We found that YAP regulates the expression of Hoxa1 and Hoxc13 in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested that Hoxa1 and Hoxc13 are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulate Hoxa1 and Hoxc13 expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans. Y es-associated protein (YAP) is a key transcriptional coactivator of the Hippo signaling pathway that plays pivotal roles in stem/progenitor cell proliferation and organ size control (1-11). YAP has also been shown to be a candidate oncogene in the development and progression of multiple human cancers (12-14). The activity of YAP is negatively regulated by its upstream kinase cascade (MstI/2, Sav1, Lats1/2, and Mob1), which leads to the phosphorylation and subsequent degradation of YAP and its paralog TAZ. Inhibition of Hippo signaling relieves YAP and TAZ, which can then translocate into the nucleus. In the nucleus, YAP or TAZ associates with TEAD or other transcription factors to activate the transcription of its target genes (15-18). Conventional knockout of Yap in mice causes early embryonic lethality due to defects in yolk sac vasculogenesis (19). Overexpression of YAP results in enlarged organ size in Drosophila and in mice with profound cell proliferation and inhibition of apoptosis (1,2,7,11, 20). In addition, YAP also plays a critical role in maintaining mouse embryonic stem cell pluripotency and regulating tissue-specific progenitor cells (21).Although the core components of the Hippo pathway are highly conserved between Drosophila and mammalian systems, the transcriptional outputs differ greatly depending on when and where the pathway is deployed. For example, overexpression of YAP in the mouse small intestine leads to Notch-dependent hyperplasia and loss of terminally differentiated cell types but does not appreciably increase the overall size of the organ (1). In Drosophila, the YAP ortholog Yki induces the expression of cycE, diap1, and bantam microRNA (11, 22). In mammalian cells, YAP induces ...