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Hippo pathway interacts with Wnt pathway to regulate the neural crest cells

The neural crest (NC) cells are migratory multipotent cells during embryogenesis, which differentiate into various derivatives and contribute significantly to tissues and organs. The Hippo pathway is a conserved anti‐growth fundamental pathway, yet its role in NC remains poorly understood. We found that Hippo pathway plays pivotal roles in NC cells proliferation, migration and differentiation, based on data obtained from comprehensive studies using in vivo NC conditional knock‐out mouse models and in vitro NC cells. Deficiency of Hippo effectors Yap and Taz caused defects in NC‐derived structures in mice such as vascular and cranial bone defects, as well as failure of NC cells to proliferate, migrate and differentiate. Notably, our motif analysis of ATAC‐seq (assay for transposase‐accessible chromatin with high‐throughput sequencing) data in mouse craniofacial tissues and human NC cells indicated that genome‐wide, 38.9% genes have enriched Tead (Yap/Taz cofactor) motifs are also enriched in Tcf/Lef (β‐catenin cofactors) motifs, suggesting that Hippo interacts with Wnt to coordinately regulate gene expression in NC cells. Wnt‐β‐catenin pathway, another fundamental pathway, has been shown to play a key role in NC cells. Our co‐IP data uncovered a direct interaction between Yap/Taz and β‐catenin in NC cells. Furthermore, our RNA‐seq data in mouse craniofacial tissues and Reverse Phase Protein Array (RPPA) data in mouse NC cells indicated that many known Wnt target genes important for cell migration and fate determination were also regulated by Yap/Taz. In addition, Yap/Taz‐Tead and Tcf/Lef‐β‐catenin complexes coordinately and directly regulate the expression of these genes. Together, our findings uncover novel roles of hippo‐Yap pathway in regulating NC cells, which partially functions through interaction with Wnt‐β‐catenin pathway.