Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation.
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 the mouse model 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. We demonstrate for the first time the central role of Ras signaling in enamel formation in CS individuals and present the mouse incisor as a model system to dissect the roles of the Ras effector pathways in vivo.
Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology.
Alice F
AF
Goodwin
William E
WE
Tidyman
Andrew H
AH
Jheon
Amnon
A
Sharir
Xu
X
Zheng
Cyril
C
Charles
James A
JA
Fagin
Martin
M
McMahon
Thomas G H
TG
Diekwisch
Bernhard
B
Ganss
Katherine A
KA
Rauen
Ophir D
OD
Klein
D000293:Adolescent; D000328:Adult; D000565:Ameloblasts / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016022:Case-Control Studies; D016764:Cell Polarity; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D056685:Costello Syndrome / Q000235:genetics / Q000378:metabolism*; D003743:Dental Enamel / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007223:Infant; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
D004791:Enzyme Inhibitors; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); C501009:HRAS protein, human