Abnormal ras signaling in costello syndrome (CS) negatively regulates enamel formation

Alice F. Goodwin, William E. Tidyman, Andrew H. Jheon, Amnon Sharir, Xu Zheng, Cyril Charles, James A. Fagin, Martin McMahon, Thomas G.H. Diekwisch, Bernhard Ganss, Katherine A. Rauen, Ophir D. Klein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


RASopathies are syndromes caused by gain-of-function mutations in the Ras signaling pathway.One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities. We report that a majority of individuals with CS have hypo-mineralization of enamel, the outer covering of teeth, and that similar defects are present in a CS mouse model. Comprehensive analysis of themousemodel revealed that ameloblasts, the cells that generate enamel, lacked polarity, and the ameloblast progenitor cells were hyperproliferative. Ras signals through two main effector cascades, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. To determine through which pathway Ras affects enamel formation, inhibitors targeting either PI3K or MEK 1 and 2 (MEK 1/2), kinases in the MAPK pathway, were utilized. MEK1/2 inhibition rescued the hypo-mineralized enamel, normalized the ameloblast polarity defect and restored normal progenitor cell proliferation. In contrast, PI3K inhibition only corrected the progenitor cell proliferation phenotype.Wedemonstrate for thefirst time the central role of Ras signaling in enamel formation in CS individuals and present themouse incisor as amodel system to dissect the roles of the Ras effector pathways in vivo.

Original languageAmerican English
Article numberddt455
Pages (from-to)682-692
Number of pages11
JournalHuman Molecular Genetics
Issue number3
StatePublished - Feb 2014
Externally publishedYes

Bibliographical note

Funding Information:
The authors are funded in part by fellowships and grants from the National Institutes of Health (F30-DE022205 to A.F.G., K99-DE022059 to A.H.J., R01-AR062165 to K.A.R. and R01-DE021420 and DP2-OD00719 to O.D.K.), Canadian Institutes of Health Research (MOP-119310 to B.G.) and Natural Sciences and Engineering Research Council of Canada (RGPIN-403292-11 to B.G.).


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