YAP Regulates the Expression of Hoxa1 and Hoxc13 in Mouse and Human Oral and Skin Epithelial Tissues

Abstract

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 ...

Systems biology of facial development: contributions of ectoderm and mesenchyme

“…Amot is part of the tension-sensing junctional complexes, while Vgll2 is a transcriptional cofactor (Maeda et al, 2002). In the facial ectoderm the Hippo pathway promotes proliferation in maturing skin and oral epithelia (Liu et al, 2015) and signaling that is necessary for survival of the underlying mesenchyme (Johnson et al, 2011). This raises the possibility that tension within the ectoderm, sensed by the Hippo pathway, might be important for coordinating growth of the mesenchyme with that of the overlying ectoderm.…”

Role of the Wnt signaling molecules in the tooth

“…In transgenic mice that overexpress a constitutively active form of YAP in the dental epithelium, the resulting tooth phenotype was deformed tooth morphogenesis with widened dental lamina [105]. In contrast, YAP deficiency in the dental epithelium resulted in development of a small tooth germ with reduced epithelial cell proliferation [106]. Data from the gene expression profiles of an embryonic E14.5 YAP conditional knockout and YAP transgenic mouse tooth germs indicate that YAP regulates the expression of Hoxa1 and Hoxc13 in oral as well as dental epithelial tissues [106].…”

“…In contrast, YAP deficiency in the dental epithelium resulted in development of a small tooth germ with reduced epithelial cell proliferation [106]. Data from the gene expression profiles of an embryonic E14.5 YAP conditional knockout and YAP transgenic mouse tooth germs indicate that YAP regulates the expression of Hoxa1 and Hoxc13 in oral as well as dental epithelial tissues [106]. However, the relationship between Wnt signaling and YAP/TAZ in tooth formation remains to be determined.…”

Inhibition of CXCR4 regulates epithelial mesenchymal transition of NSCLC via the Hippo‐YAP signaling pathway

“…For example, the Hippo pathway (the Salvador‐Warts‐Hippo) is correlated with the renewal and differentiation of stem cells and it has been identified as a critical link of oncogenic transformation in NSCLC (You et al, ). In fact, YAP, as a Hippo signaling transcriptional coactivator, can greatly affect the proliferation of stem cells, the control of organ size, and the development of tumors through the regulation of downstream transcriptional target genes Ctgf and Birc5/surviving (Liu et al, ; Yeung et al, ). Additionally, a recent study reported that YAP transcriptional activity was associated with the metastasis of lung cancer (Huang et al, ).…”