Journal article
FoxO6 regulates Hippo signaling and growth of the craniofacial complex
PLoS genetics, Vol.14(10), pp.e1007675-e1007675
10/2018
DOI: 10.1371/journal.pgen.1007675
PMCID: PMC6197693
PMID: 30286078
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.
Details
- Title: Subtitle
- FoxO6 regulates Hippo signaling and growth of the craniofacial complex
- Creators
- Zhao Sun - Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaClarissa S G da Fontoura - Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA, United States of AmericaMyriam Moreno - Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaNathan E Holton - Department of Orthodontics, College of Dentistry, The University of Iowa, Iowa City, IA, United States of AmericaMason Sweat - Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaYan Sweat - Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaMyoung Keun Lee - Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh PA, United States of AmericaJed Arbon - Private practice, Cary, North Carolina United States of AmericaFelicitas B Bidlack - The Forsyth Institute, Cambridge, MA United States of AmericaDaniel R Thedens - Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaPeggy Nopoulos - Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaHuojun Cao - Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA, United States of AmericaSteven Eliason - Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States of AmericaSeth M Weinberg - Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh PA, United States of AmericaJames F Martin - Baylor College of MedicineLina Moreno-Uribe - Department of Orthodontics, College of Dentistry, The University of Iowa, Iowa City, IA, United States of AmericaBrad A Amendt - Department of Orthodontics, College of Dentistry, The University of Iowa, Iowa City, IA, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.14(10), pp.e1007675-e1007675
- DOI
- 10.1371/journal.pgen.1007675
- PMID
- 30286078
- PMCID
- PMC6197693
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- United States
- Grant note
- T32 DE014678 / NIDCR NIH HHS\r\nT90 DE023520 / NIDCR NIH HHS\r\nU01 DE020078 / NIDCR NIH HHS\r\nHHSN268201200008I / NHLBI NIH HHS\r\nR01 DE027023 / NIDCR NIH HHS\r\nR01 DE016148 / NIDCR NIH HHS
- Language
- English
- Date published
- 10/2018
- Academic Unit
- Neurology; Electrical and Computer Engineering; Psychiatry; Anthropology; Craniofacial Anomalies Research Center; Roy J. Carver Department of Biomedical Engineering; Radiology; Orthodontics; Anatomy and Cell Biology; Endodontics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Dental Research
- Record Identifier
- 9983983670502771
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