FoxO6 Regulates Hippo Signaling to Control Face Morphology

Hippo signaling controls tissue growth and organ size but, its role in development of the craniofacial structures is unknown. We demonstrate that tissue specific Hippo signaling regulates growth of the face and is a crucial component in determining human facial characteristics. We have identified the transcriptional factor FoxO6 as an activator of Hippo signaling with specific expression in craniofacial tissues. FoxO6 loss‐of‐function mice undergo expansion of the face and skull, enlargement of the mandible and maxilla and lengthening of the incisors associated with increases in cell proliferation. FoxO6 activates Lats1 /2 expression, thereby increasing Yap phosphorylation to control Hippo signaling. A phenotype‐genotype correlation test identified significant associations (p<0.001) with three FOXO6 human single nucleotide polymorphisms in Caucasian adults with dento‐skeletal bite problems ranging from retrognathism to prognathism of both jaws. One mutation creates a new cFOS binding element in the FOXO6 5′flanking region that increases FOXO6 expression. This mutation is associated with bimaxillary retrusion and correlates with the role of FOXO6 and Hippo signaling. FoxO6 −/− mice also exhibited decreases in the expression of Shh and Runx2, suggesting that these factors are linked to Hippo signaling. Together, these results identify a FoxO6‐Hippo regulatory pathway that controls skull growth, odontogenesis and face morphology. These data suggest that human FOXO6 mutations explain differences in the human face form.