ArticleHuman molecular genetics2014
Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
29 citing papers in PubMed, 41 citations in OpenAlex.
- Ameloblastin amphipathic helix motif mediates ameloblast polarization and prismatic enamel formation.International journal of oral science · 2026Article
- Higher caries experience in individuals with neurofibromatosis 1: a matched case-control study.Clinical oral investigations · 2026Article
- Ameloblastin Amphipathic Helix Motif mediates Ameloblast Polarization and Prismatic Enamel Formation via a RhoA Signaling Pathway.Research square · 2026Article
- Review
- Review
- The intricacies of tooth enamel: Embryonic origin, development and human genetics.Journal of structural biology · 2024Review
- Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.Life (Basel, Switzerland) · 2024Review
- Article
- MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.Neuro-oncology · 2022Review
- Review
- Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs.Stem cell reports · 2021Article
- The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors.Frontiers in oral health · 2021Review
- New insight into dental epithelial stem cells: Identification, regulation, and function in tooth homeostasis and repair.World journal of stem cells · 2020Review
- Costello syndrome model mice with a HrasCell death & disease · 2020Article
- Costello syndrome: Clinical phenotype, genotype, and management guidelines.American journal of medical genetics. Part A · 2019Article
- KRAS mutations drive adenomatoid odontogenic tumor and are independent of clinicopathological features.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2019Article
- Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.Acta neuropathologica · 2018Article
- The Role of Fibroblast Growth Factors in Tooth Development and Incisor Renewal.Stem cells international · 2018Review
- Differential expression of transforming growth factor-beta1, connective tissue growth factor, phosphorylated-SMAD2/3 and phosphorylated-ERK1/2 during mouse tooth development.Journal of molecular histology · 2017Article
- Meeting report: a hard look at the state of enamel research.International journal of oral science · 2017Article
Corrections and comments
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Authors and funding
12 authors at 7 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.