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FoxO6 regulates Hippo signaling and growth of the craniofacial complex
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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197693/ https://www.ncbi.nlm.nih.gov/pubmed/30286078 http://dx.doi.org/10.1371/journal.pgen.1007675 |
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author | Sun, Zhao da Fontoura, Clarissa S. G. Moreno, Myriam Holton, Nathan E. Sweat, Mason Sweat, Yan Lee, Myoung Keun Arbon, Jed Bidlack, Felicitas B. Thedens, Daniel R. Nopoulos, Peggy Cao, Huojun Eliason, Steven Weinberg, Seth M. Martin, James F. Moreno-Uribe, Lina Amendt, Brad A. |
author_facet | Sun, Zhao da Fontoura, Clarissa S. G. Moreno, Myriam Holton, Nathan E. Sweat, Mason Sweat, Yan Lee, Myoung Keun Arbon, Jed Bidlack, Felicitas B. Thedens, Daniel R. Nopoulos, Peggy Cao, Huojun Eliason, Steven Weinberg, Seth M. Martin, James F. Moreno-Uribe, Lina Amendt, Brad A. |
author_sort | Sun, Zhao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6197693 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61976932018-11-05 FoxO6 regulates Hippo signaling and growth of the craniofacial complex Sun, Zhao da Fontoura, Clarissa S. G. Moreno, Myriam Holton, Nathan E. Sweat, Mason Sweat, Yan Lee, Myoung Keun Arbon, Jed Bidlack, Felicitas B. Thedens, Daniel R. Nopoulos, Peggy Cao, Huojun Eliason, Steven Weinberg, Seth M. Martin, James F. Moreno-Uribe, Lina Amendt, Brad A. PLoS Genet Research Article 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. Public Library of Science 2018-10-04 /pmc/articles/PMC6197693/ /pubmed/30286078 http://dx.doi.org/10.1371/journal.pgen.1007675 Text en © 2018 Sun et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Sun, Zhao da Fontoura, Clarissa S. G. Moreno, Myriam Holton, Nathan E. Sweat, Mason Sweat, Yan Lee, Myoung Keun Arbon, Jed Bidlack, Felicitas B. Thedens, Daniel R. Nopoulos, Peggy Cao, Huojun Eliason, Steven Weinberg, Seth M. Martin, James F. Moreno-Uribe, Lina Amendt, Brad A. FoxO6 regulates Hippo signaling and growth of the craniofacial complex |
title | FoxO6 regulates Hippo signaling and growth of the craniofacial complex |
title_full | FoxO6 regulates Hippo signaling and growth of the craniofacial complex |
title_fullStr | FoxO6 regulates Hippo signaling and growth of the craniofacial complex |
title_full_unstemmed | FoxO6 regulates Hippo signaling and growth of the craniofacial complex |
title_short | FoxO6 regulates Hippo signaling and growth of the craniofacial complex |
title_sort | foxo6 regulates hippo signaling and growth of the craniofacial complex |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197693/ https://www.ncbi.nlm.nih.gov/pubmed/30286078 http://dx.doi.org/10.1371/journal.pgen.1007675 |
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