Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation

Hum Mol Genet. 2014 Feb 1;23(3):682-92. doi: 10.1093/hmg/ddt455. Epub 2013 Sep 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Ameloblasts / metabolism
  • Ameloblasts / pathology
  • Animals
  • Case-Control Studies
  • Cell Polarity
  • Child
  • Child, Preschool
  • Cohort Studies
  • Costello Syndrome / genetics
  • Costello Syndrome / metabolism*
  • Dental Enamel / drug effects
  • Dental Enamel / metabolism
  • Dental Enamel / pathology*
  • Dental Enamel / ultrastructure
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Infant
  • MAP Kinase Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 1 / metabolism
  • Male
  • Mice
  • Mice, Mutant Strains
  • Microscopy, Electron, Scanning
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction / genetics
  • Young Adult

Substances

  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • MAP Kinase Kinase Kinase 1
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)