Phenotypic and evolutionary implications of modulating the ERK-MAPK cascade using the dentition as a model

Marangoni, Pauline; Charles, Cyril; Tafforeau, Paul; Laugel-Haushalter, Virginie; Joo, Adriane; Bloch‐Zupan, Agnès; Klein, Ophir D.; Viriot, Laurent

doi:10.1038/srep11658

Cited by 21 publications

(28 citation statements)

References 50 publications

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“…Their expression is induced upon growth factor stimulation, and the protein products inhibit FGFR‐mediated activation of the ERK‐MAPK signaling pathway . In the mouse, Spry2 and Spry4 prevent the development of supernumerary teeth, and Spry1 , Spry2 , and Spry4 are required for correct molar cusp patterning . In the mouse incisor, which is a continuously growing tooth, Spry2 and Spry4 restrict the differentiation of enamel‐secreting ameloblasts to the labial side, allowing asymmetric enamel deposition …”

Section: Introductionmentioning

confidence: 99%

“…(17) In the mouse, Spry2 and Spry4 prevent the development of supernumerary teeth, (7) and Spry1, Spry2, and Spry4 are required for correct molar cusp patterning. (18,19) In the mouse incisor, which is a continuously growing tooth, Spry2 and Spry4 restrict the differentiation of enamel-secreting ameloblasts to the labial side, allowing asymmetric enamel deposition. (20) Here, to further investigate the roles of the FGF signaling pathway in odontogenesis, we utilized a transgenic mouse line (K14-Spry4) in which the expression of mouse Spry4 is driven in the epithelium of many ectodermal organs under the control of the human keratin-14 promoter.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar

et al. 2019

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FGF signaling plays a critical role in tooth development, and mutations in modulators of this pathway produce a number of striking phenotypes. However, many aspects of the role of the FGF pathway in regulating the morphological features and the mineral quality of the dentition remain unknown. Here, we used transgenic mice overexpressing the FGF negative feedback regulator Sprouty4 under the epithelial keratin 14 promoter (K14‐ Spry4 ) to achieve downregulation of signaling in the epithelium. This led to highly penetrant defects affecting both cusp morphology and the enamel layer. We characterized the phenotype of erupted molars, identified a developmental delay in K14‐ Spry4 transgenic embryos, and linked this with changes in the tooth developmental sequence. These data further delineate the role of FGF signaling in the development of the dentition and implicate the pathway in the regulation of tooth mineralization. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar

et al. 2019

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“…3 F, green arrowhead, Supplementary Table S3 ). While typically rodent ectopic 4th molars arise in the diastema 22 , 23 , Smoc2 −/− ectopic molars are exclusively distal (adjacent to 3rd molars), similar to Wnt10a mutants also displaying supernumerary mandibular 4th molars 24 . Roots are also consistency reduced in size, displaying taping shorter shapes (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 84%

Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss

Morkmued¹,

Clauss²,

Schuhbaur³

et al. 2020

Sci Rep

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Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components (Odontogenic ameloblast-associated protein) and dentin dysplasia targets (Dentin matrix acidic phosphoprotein 1). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2−/− mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2−/− mutants, reducing matrix metalloprotease (Mmp)9. Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.

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“…It is also possible that variation in genetic background accounts for variation in the penetrance of tooth phenotypes associated with these Sprouty null mutations (Marangoni et al 2015). Understanding why certain backgrounds display higher resilience or opposite phenotypic effects is valuable in the search for genes and genetic pathways associated with variation in the phenotypic results of known disease alleles.…”

Section: Discussionmentioning

confidence: 99%

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape

Percival

Marangoni

Tapaltsyan

et al. 2017

G3 Genes|Genomes|Genetics

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Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2. While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice.

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Phenotypic and evolutionary implications of modulating the ERK-MAPK cascade using the dentition as a model

Cited by 21 publications

References 50 publications

Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar

Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar

Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape

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