FoxO6 regulates Hippo signaling and growth of the craniofacial complex

Abstract

The mechanisms that regulate post-natal growth of the craniofacial complex and that ultimately determine the size and shape of our faces are not well understood. Hippo signaling is a general mechanism to control tissue growth and organ size, and although it is known that Hippo signaling functions in neural crest specification and patterning during embryogenesis and before birth, its specific role in postnatal craniofacial growth remains elusive. We have identified the transcription factor FoxO6 as an activator of Hippo signaling regulating neonatal growth of the face. During late stages of mouse development, FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Enlargement of the mandible and maxilla and lengthening of the incisors in FoxO6-/- mice are associated with increases in cell proliferation. In vitro and in vivo studies demonstrated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling. FoxO6-/- mice have significantly reduced Hippo Signaling caused by a decrease in Lats1 expression and decreases in Shh and Runx2 expression, suggesting that Shh and Runx2 are also linked to Hippo signaling. In vitro, FoxO6 activates Hippo reporter constructs and regulates cell proliferation. Furthermore PITX2, a regulator of Hippo signaling is associated with Axenfeld-Rieger Syndrome causing a flattened midface and we show that PITX2 activates FoxO6 expression. Craniofacial specific expression of FoxO6 postnatally regulates Hippo signaling and cell proliferation. Together, these results identify a FoxO6-Hippo regulatory pathway that controls skull growth, odontogenesis and face morphology.

The Roles of FoxO Transcription Factors in Regulation of Bone Cells Function

“…The four FoxO protein members share obvious sequence homology and possess four clearly different functional motifs, which include a forkhead domain, nuclear localization, nuclear export, and transactivation domains ( Figure 1) [12,13]. All the four FoxO members are ubiquitously expressed [14], including FoxO6 that was previously reported to exist basically in the brain but has been more recently discovered in other organs as well [4,15]. In particular, FoxO1, FoxO4, and FoxO6 are more detected in the adipose, musculoskeletal, and nervous tissues, respectively, while FoxO3 is more expressed in the stomach, spleen, kidney, intestine, and cardiac tissues [13].…”

Simultaneous discovery of candidate imprinted genes and Imprinting Control Regions in the mouse genome

“…Even though both FOXO6 and POU3F1 are transcription factors, they play distinguishable roles in the regulation of gene expression. Foxo6 is expressed at late stages of face development [71]. Foxo6 -/mice underwent expansion of the face, frontal cortex, olfactory component and skull [71].…”

“…Foxo6 is expressed at late stages of face development [71]. Foxo6 -/mice underwent expansion of the face, frontal cortex, olfactory component and skull [71]. Pou3f1 plays a role in spermatogenesis [72].…”

“…Cited2 impacts left-right patterning of the body' s axis [33]. Functions of FOXO6 include regulation of Hippo signaling and the growth of the craniofacial complex [71]. In the context of organogenesis, we obtained Maml3.…”

“…This gene encodes a transcription factor. Its functions include regulation of Hippo signaling and growth of the craniofacial complex[71].______________________________________________________________________________________ Fig. S23.…”