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

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

doi:10.1093/hmg/ddt455

Cited by 36 publications

(36 citation statements)

References 58 publications

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“…Bifid uvula, gingival hypertrophy and thickening of the alveolar ridge have also been reported in CS. Additionally, CS individuals have delayed tooth development and eruption and a unique enamel defect characterized by thin, hypomineralized enamel …”

Section: Introductionmentioning

confidence: 99%

A review of craniofacial and dental findings of the RASopathies

Cao

Alrejaye

Klein

et al. 2017

Orthod Craniofacial Res

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Objectives The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS); Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome); neurofibromatosis type 1 (NF1); Costello syndrome (CS); cardio-facio-cutaneous (CFC) syndrome; neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome); and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analyzed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. Methods Review of the literature. Results Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics. Conclusions Careful description of craniofacial and dental features in the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signaling in craniofacial development.

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Section: Introductionmentioning

confidence: 99%

A review of craniofacial and dental findings of the RASopathies

Cao

Alrejaye

Klein

et al. 2017

Orthod Craniofacial Res

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Section: Introductionmentioning

confidence: 99%

“…Proteolytic cleavage and shedding of its extracellular domain can spread FGF signaling to adjacent cells, thus regulating the local reception of FGF signaling activity (7). Its cytoplasmic domains can also initiate FGF-induced signaling independently of FGFRs through the activation of Rho GTPases, such as Rac1, which plays an essential role in the dental epithelium, involving cell-matrix interactions and matrix biomineralization (8,9).FGF signaling plays critical roles in tooth development (10). In molar tooth development, FGF4, 8 and 9 act as epithelial signals, mediating inductive interactions between the dental epithelium and the mesenchyme during the initiation of tooth development and the regulation of tooth shape (11).…”

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confidence: 99%

Expression and roles of syndecan-4 in dental epithelial cell differentiation

Zhang

Yang

Sun

et al. 2014

International Journal of Molecular Medicine

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Abstract. Syndecan-4 (SDC4), a transmembrane heparan sulfate proteoglycan, acts as a signal transducer. It affects the growth and differentiation of a number of tissues and organs. However, the specific mechanisms through which SDC4 regulates the differentiation of dental epithelial cells (amelogenesis) and tooth development remains largely unknown. In the present study, to identify the SDC4-regulated processes in dental epithelial cells, the SDC4 expression pattern was examined in mouse molar and postnatal incisor tooth germs during the late bell stage of development. Small interfering RNA (siRNA) was designed for this study and used to downregulate SDC4 expression in the rat dental epithelial cell line, HAT-7. The results revealed that SDC4 was mainly present in the oral epithelium, the dental epithelial cells of enamel organs in the molars and the cervical loops in the incisors. When the inner enamel epithelial cells gave rise to ameloblasts, however, the loss of SDC4 expression was evident. SDC4 was also expressed in stratum intermedium (SI) cells in the incisors and in dental mesenchymal cells adjacent to the cervical loops in molars (E18) and postnatal incisors. Fibroblast growth factor 10 (FGF10) promoted proliferation and slightly decreased cell differentiation. The knockdown of SDC4 using specific siRNA led to a decrease in cell proliferation and a highly significant increase in amelogenin, ameloblastin, kallikrein 4 and matrix metalloproteinase 20 expression, molecules that are known to participate in the formation of enamel. These effects were attenuated by FGF10, which upregulated SDC4 expression. Taken together, these results suggest that SDC4 participates in amelogenesis, and FGF10 may modulate dental epithelial cell behaviors through the regulation of SDC4 expression. IntroductionSyndecan (SDC)4 is a cell surface heparan sulfate proteoglycan (HSPG). Its heparan sulfate (HS) chains and core protein could control the stability, movement and reception of diffusible heparin-binding growth factors (1). In addition, it can form physical connections between the extracellular matrix (ECM) and intracellular signaling to affect the growth and differentiation of a number of tissues and organs (2,3). SDC4 is highly complex by virtue of its external side chains, and thus interacts with a variety of ligands, such as vascular endothelial growth factors (VEGFs), platelet-derived growth factors (PDGFs) and fibroblast growth factors (FGFs) (4). At the cell membrane, SDC4 stabilizes the interactions between ligands and receptors by forming a ternary complex, which has been demonstrated in several signaling pathways (5,6). Proteolytic cleavage and shedding of its extracellular domain can spread FGF signaling to adjacent cells, thus regulating the local reception of FGF signaling activity (7). Its cytoplasmic domains can also initiate FGF-induced signaling independently of FGFRs through the activation of Rho GTPases, such as Rac1, which plays an essential role in the dental epithelium, involving cell-matrix interactio...

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“…Interestingly, these mice developed tumors, including papillomas and angiosarcomas, a distinctive feature of CS individuals [ 137 ]. Interestingly, MEK inhibitor treatment rescued enamel defects (hypo-mineralization) and both MEK inhibitor and PI3K inhibitor corrected the disorganized growth of ameloblasts by normalizing progenitor cell proliferation [ 140 ].…”

Section: H -Rasmentioning

confidence: 99%

Modeling RASopathies with Genetically Modified Mouse Models

Hernández-Porras

Guerra

2016

Methods in Molecular Biology

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The RAS/MAPK signaling pathway plays key roles in development, cell survival and proliferation, as well as in cancer pathogenesis. Molecular genetic studies have identified a group of developmental syndromes, the RASopathies, caused by germ line mutations in this pathway. The syndromes included within this classification are neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS, NF1-like syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and hereditary gingival fibromatosis (HGF) type 1. Although these syndromes present specific molecular alterations, they are characterized by a large spectrum of functional and morphological abnormalities, which include heart defects, short stature, neurocognitive impairment, craniofacial malformations, and, in some cases, cancer predisposition. The development of genetically modified animals, such as mice (Mus musculus), flies (Drosophila melanogaster), and zebrafish (Danio rerio), has been instrumental in elucidating the molecular and cellular bases of these syndromes. Moreover, these models can also be used to determine tumor predisposition, the impact of different genetic backgrounds on the variable phenotypes found among the patients and to evaluate preventative and therapeutic strategies. Here, we review a wide range of genetically modified mouse models used in the study of RASopathies and the potential application of novel technologies, which hopefully will help us resolve open questions in the field.

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

Cited by 36 publications

References 58 publications

A review of craniofacial and dental findings of the RASopathies

A review of craniofacial and dental findings of the RASopathies

Expression and roles of syndecan-4 in dental epithelial cell differentiation

Modeling RASopathies with Genetically Modified Mouse Models

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