Meckel's Cartilage in Mandibular Development and Dysmorphogenesis

M Kathleen Pitirri, Emily L Durham, Natalie A Romano, Jacob I Santos, Abigail P Coupe, Hao Zheng, Danny Z Chen, Kazuhiko Kawasaki, Ethylin Wang Jabs, Joan T Richtsmeier, Meng Wu, Susan M Motch Perrine, M Kathleen Pitirri, Emily L Durham, Natalie A Romano, Jacob I Santos, Abigail P Coupe, Hao Zheng, Danny Z Chen, Kazuhiko Kawasaki, Ethylin Wang Jabs, Joan T Richtsmeier, Meng Wu, Susan M Motch Perrine

Abstract

The Fgfr2c C342Y/+ Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in the fibroblast growth factor receptor 2 (Fgfr2) gene equivalent to a FGFR2 mutation commonly associated with Crouzon and Pfeiffer syndromes in humans. The Fgfr2c C342Y mutation results in constitutive activation of the receptor and is associated with upregulation of osteogenic differentiation. Fgfr2cC342Y/+ Crouzon syndrome mice show premature closure of the coronal suture and other craniofacial anomalies including malocclusion of teeth, most likely due to abnormal craniofacial form. Malformation of the mandible can precipitate a plethora of complications including disrupting development of the upper jaw and palate, impediment of the airway, and alteration of occlusion necessary for proper mastication. The current paradigm of mandibular development assumes that Meckel's cartilage (MC) serves as a support or model for mandibular bone formation and as a template for the later forming mandible. If valid, this implies a functional relationship between MC and the forming mandible, so mandibular dysmorphogenesis might be discerned in MC affecting the relationship between MC and mandibular bone. Here we investigate the relationship of MC to mandible development from the early mineralization of the mandible (E13.5) through the initiation of MC degradation at E17.7 using Fgfr2c C342Y/+ Crouzon syndrome embryos and their unaffected littermates (Fgfr2c +/+ ). Differences between genotypes in both MC and mandibular bone are subtle, however MC of Fgfr2c C342Y/+ embryos is generally longer relative to unaffected littermates at E15.5 with specific aspects remaining relatively large at E17.5. In contrast, mandibular bone is smaller overall in Fgfr2c C342Y/+ embryos relative to their unaffected littermates at E15.5 with the posterior aspect remaining relatively small at E17.5. At a cellular level, differences are identified between genotypes early (E13.5) followed by reduced proliferation in MC (E15.5) and in the forming mandible (E17.5) in Fgfr2c C342Y/+ embryos. Activation of the ERK pathways is reduced in the perichondrium of MC in Fgfr2c C342Y/+ embryos and increased in bone related cells at E15.5. These data reveal that the Fgfr2c C342Y mutation differentially affects cells by type, location, and developmental age indicating a complex set of changes in the cells that make up the lower jaw.

Keywords: Crouzon syndrome; craniofacial development; embryonic bone; embryonic cartilage; fibroblast growth factor; lower jaw; mandible; skull.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Pitirri, Durham, Romano, Santos, Coupe, Zheng, Chen, Kawasaki, Jabs, Richtsmeier, Wu and Motch Perrine.

Figures

FIGURE 1
FIGURE 1
Schematic of MC in mandible identifying regions for analysis. Example histological sections (top) associated with developing mandible and MC (bottom) (after Svandova et al., 2020). In the histological sections, mandibular bone matrix (MB) is stained green and is adjacent to the red-orange MC stained using a standard Safranin-O protocol. Below, the developing mandible (tan), segmented from microCT images, is superimposed with MC (blue) and mandibular teeth (red) segmented from PTA-enhanced microCT images of an E17.5 Fgfr2c+/+ embryo. Note that the color of MC and MB is not consistent between histological images (top) and 3D models created from PT-enhanced microCT images (bottom). MC is divided into 4 equal regions from anterior to posterior with Anterior and Mid 1 containing the break in MC at E17.5 associated with the root of the incisor (I). The incus is not included in this model.
FIGURE 2
FIGURE 2
3D landmarks on developing MC and mandible. (A) Two medial landmarks and 8, 10, or 14 bilateral landmarks shown on MC at E13.5 (top), E15.5 (middle) and E17.5 (bottom) embryos respectively. Lateral views (buccal) are displayed on the left and superior views are on the right. (B) Ten bilateral landmarks are shown on the left hemi-mandible of an E17.5 embryo. Lateral views are displayed on the left (buccal view (top) and lingual view (bottom)) and superior view of the left and right hemi-mandibles are shown on the right. Scale = 1.0 mm.
FIGURE 3
FIGURE 3
Relative orientation of MC and developing mandible in Fgfr2c+/+ and Fgfr2cC342Y/+ embryos. Segmentations of multimodal images of MC (blue) and mandibular bone (tan) of developing mandible at E13.5 (A), E15.5 (B), and E17.5 (C) with representative Fgfr2c+/+ embryos displayed in the top row and Fgfr2cC342Y/+ Crouzon syndrome embryos displayed in the bottom row of each age group. Lateral views (buccal) are displayed on the left and superior views on the right. Not enough bone is mineralized at E13.5 to be detected by microCT. Scale = 1.0 mm.
FIGURE 4
FIGURE 4
Morphological differences of MC in Fgfr2cC342Y/+ embryos and Fgfr2c+/+ littermates at E15.5 and E17.5. Linear distances that are statistically significantly different between genotypes by confidence interval testing (α = 0.10) are shown for E15.5 (A) and E17.5 (B). Thin yellow lines indicate linear distances that are between 5% and 10% larger in Fgfr2cC342Y/+ embryos as compared to Fgfr2c+/+ embryos and thicker orange lines indicate linear distances that are between 10% and 20% larger in Fgfr2cC342Y/+ embryos as compared to Fgfr2c+/+ embryos. For orientation, superimpositions of MC and mandibular bone are inset. Lateral views (buccal) are displayed on the left and superior views are on the right. Scale = 1.0 mm.
FIGURE 5
FIGURE 5
Histomorphometric analysis of MC in Fgfr2cC342Y/+ embryos and Fgfr2c+/+ littermates, E13.5, E15.5, E17.5. (A) Representative Safranin O-stained sections of MC and surrounding mandible bone (MB) in the coronal plane from Fgfr2c+/+ and Fgfr2cC342Y/+ embryos at E13.5 (top two rows), E15.5 (middle two rows) and E17.5 (bottom two rows). Chondrocytes and matrix are identified by the red-orange Safranin O stain with green bone matrix surrounding (MB). The incisor (I) is adjacent to MC and MB in Anterior and Mid 1. Scale = 0.10 mm. (B) Assessment of cross-sectional area of MC indicates some differences by genotype early in development (E13.5, top) with Fgfr2cC342Y/+ embryos having a relatively greater area overall (box plot, left) and at specific regions in the antero-posterior dimension (line plots, right). (C) Similarly, more cartilage matrix was identified at E13.5 (top) in Fgfr2cC342Y/+ embryos with no differences by genotype being noted later in development [E15.5 (middle), E17.5 (bottom)]. (D) The number of chondrocytes within MC did not vary by genotype at either E13.5 (top) or E15.5 (middle), but fewer chondrocytes were counted in Posterior of Fgfr2cC342Y/+ embryos at E17.5 (bottom). (E) The average diameter of chondrocytes varied little from anterior to posterior aspects of MC and not at all by genotype at E13.5 (top) and E15.5 (middle). Chondrocytes in Anterior of E17.5 Fgfr2cC342Y/+ embryos were smaller than those in Fgfr2c+/+ embryos (bottom two rows). White bar in box plot identifies median. X in box plot identifies mean. n = 3 individuals per genotype per age with at least 4 images per region per embryo being analyzed. **p ≤ 0.01, ***p ≤ 0.001.
FIGURE 6
FIGURE 6
Effect of Fgfr2c C342Y mutation on proliferation in and around MC in E15.5 and E17.5 embryos. (A) Representative coronal sections of MC and surrounding mandible bone (MB) in Fgfr2c+/+ and Fgfr2cC342Y/+ embryos stained with Proliferating Cell Nuclear Antigen (PCNA, brown stain) counterstained with hematoxylin (purple) at E15.5 (top rows) and E17.5 (bottom rows). Scale = 0.1 mm. Note that due to variation in the location of the natural break in MC, only a small remnant of MC remains in Mid 1 at E17.5 in the displayed image of an Fgfr2c+/+ embryo. (B) Quantification of proliferating cells in MC (top 2 rows) and mandible (bottom 2 rows) standardized by the total number of cells within each region. Proliferation was reduced in MC of Fgfr2cC342Y/+ embryos at E15.5 and in mandible of Fgfr2cC342Y/+ embryos at E17.5. White bar in box plot identifies median. X in box plot identifies mean. n = 3 individuals per age per genotype with at least 4 images per region per embryo being analyzed. *p ≤ 0.05. I = incisor; MO = molar.
FIGURE 7
FIGURE 7
Morphological differences in Fgfr2cC342Y/+ and Fgfr2c+/+ mandibular bone at E15.5 and E17.5. Results of EDMA using 3D landmark coordinates of 14 anatomical landmarks at E15.5 (A) and 20 anatomical landmarks at E17.5 (B) show linear distances within each model that are significantly smaller by at least 5% between genotypes. Lateral views (buccal) at left and superior views at right. Thin pink lines indicate linear distances that are decreased by 5%–10% in Fgfr2cC342Y/+ embryos, and thick purple lines indicate linear distances that are reduced by 10%–23% in Fgfr2cC342Y/+ embryos. For orientation, superimpositions of MC and mandibular bone are inset. Scalebar = 1.0 mm.
FIGURE 8
FIGURE 8
Immunohiostochemical analysis of osteoblasts and osteoclasts in developing mandible of Fgfr2cC342Y/+ embryos and Fgfr2c+/+ littermates. (A,C) Representative coronal sections of MC and surrounding mandible in Fgfr2c+/+ (top rows) and Fgfr2cC342Y/+ (bottom rows) embryos stained with alkaline phosphatase (ALP, (A) and Tartrate-Resistant Acid Phosphatase (TRAP, (C) at E15.5 (top) and E17.5 (bottom). Reduced TRAP staining can be noted in Fgfr2cC342Y/+ images especially at Mid 1. (B) Quantification of ALP positive osteoblasts in the developing mandible standardized by the total number of cells within bone matrix. (D) Count of TRAP positive multi-nucleate osteoclasts in the mandible bone matrix. White bar in box plot identifies median. X in box plot identifies mean. n = 3 individuals per age per genotype with at least 4 images per region per embryo being analyzed. * = p ≤ 0.05.
FIGURE 9
FIGURE 9
ERK pathway activation in the lower jaw of Fgfr2c+/+ and Fgfr2cC342Y/+ embryos at E15.5. Immunofluorescence for p-ERK1/2 in coronal sections of Fgfr2c+/+ (top) and Fgfr2cC342Y/+ (bottom) embryos at E15.5. Anterior, Mid 1, Mid 2, and Posterior indicate the regions of the lower jaw identified in Figure 1. Images in MB ROI column show higher magnification of the boxed areas in Mid 2. Arrows mark the locations of the perichondrium of MC. I, incisor; MB, mandible; MC, Meckel’s cartilage; T, tongue. n = 3 per genotype with at least 4 images per individual being analyzed. Scale = 100 µm.

References

    1. Amin S., Tucker A. S. (2006). Joint Formation in the Middle Ear: Lessons from the Mouse and guinea Pig. Dev. Dyn. 235, 1326–1333. 10.1002/dvdy.20666
    1. Azoury S. C., Reddy S., Shukla V., Deng C.-X. (2017). Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis. Int. J. Biol. Sci. 13, 1479–1488. 10.7150/ijbs.22373
    1. Baddoo M., Hill K., Wilkinson R., Gaupp D., Hughes C., Kopen G. C., et al. (2003). Characterization of Mesenchymal Stem Cells Isolated from Murine Bone Marrow by Negative Selection. J. Cel. Biochem. 89, 1235–1249. 10.1002/jcb.10594
    1. Behringer R., Gertsenstein M., Nagy K., Nagy A. (2013). Manipulating the Mouse Embryo: A Laboratory Manual. Fourth edition (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press; ). Revised edition.
    1. Boutros S., Shetye P. R., Ghali S., Carter C. R., McCarthy J. G., Grayson B. H. (2007). Morphology and Growth of the Mandible in Crouzon, Apert, and Pfeiffer Syndromes. J. Craniofac. Surg. 18, 146–150. 10.1097/01.scs.0000248655.53405.a7
    1. Breur G. J., VanEnkevort B. A., Farnum C. E., Wilsman N. J. (1991). Linear Relationship between the Volume of Hypertrophic Chondrocytes and the Rate of Longitudinal Bone Growth in Growth Plates. J. Orthop. Res. 9, 348–359. 10.1002/jor.1100090306
    1. Brewer J. R., Mazot P., Soriano P. (2016). Genetic Insights into the Mechanisms of Fgf Signaling. Genes Dev. 30, 751–771. 10.1101/gad.277137.115
    1. Chen P., Zhang L., Weng T., Zhang S., Sun S., Chang M., et al. (2014). A Ser252Trp Mutation in Fibroblast Growth Factor Receptor 2 (FGFR2) Mimicking Human Apert Syndrome Reveals an Essential Role for FGF Signaling in the Regulation of Endochondral Bone Formation. PLoS One 9, e87311. 10.1371/journal.pone.0087311
    1. Cohen M. M., Krelborg S. (1992). Birth Prevalence Studies of the Crouzon Syndrome: Comparison of Direct and Indirect Methods. Clin. Genet. 41, 12–15. 10.1111/j.1399-0004.1992.tb03620.x
    1. Cole T. (2002). WinEDMA: Software for Euclidean Distance Matrix Analysis. Kansas City: University of Missouri, School of Medicine.
    1. Cooper K. L., Oh S., Sung Y., Dasari R. R., Kirschner M. W., Tabin C. J. (2013). Multiple Phases of Chondrocyte Enlargement Underlie Differences in Skeletal Proportions. Nature 495, 375–378. 10.1038/nature11940
    1. Costaras-Volarich M., Pruzansky S. (1984). Is the Mandible Intrinsically Different in Apert and Crouzon Syndromes? Am. J. Orthod. 85, 475–487. 10.1016/0002-9416(84)90087-3
    1. Deckelbaum R. A., Holmes G., Zhao Z., Tong C., Basilico C., Loomis C. A. (2012). Regulation of Cranial Morphogenesis and Cell Fate at the Neural Crest-Mesoderm Boundary by Engrailed 1. Development 139, 1346–1358. 10.1242/dev.076729
    1. Durham E. L., Howie R. N., Houck R., Oakes B., Grey Z., Hall S., et al. (2018). Involvement of Calvarial Stem Cells in Healing: A Regional Analysis of Large Cranial Defects. Wound Rep. Reg. 26, 359–365. 10.1111/wrr.12658
    1. Durham E., Howie R. N., Larson N., LaRue A., Cray J. (2019). Pharmacological Exposures May Precipitate Craniosynostosis through Targeted Stem Cell Depletion. Stem Cel Res. 40, 101528. 10.1016/j.scr.2019.101528
    1. Eswarakumar V. P., Horowitz M. C., Locklin R., Morriss-Kay G. M., Lonai P. (2004). A Gain-Of-Function Mutation of Fgfr2c Demonstrates the Roles of This Receptor Variant in Osteogenesis. Proc. Natl. Acad. Sci. U.S.A. 101, 12555–12560. 10.1073/pnas.0405031101
    1. Frisdal A., Trainor P. A. (2014). Development and Evolution of the Pharyngeal Apparatus. Wires Dev. Biol. 3, 403–418. 10.1002/wdev.147
    1. Graham A., Richardson J. (2012). Developmental and Evolutionary Origins of the Pharyngeal Apparatus. EvoDevo 3, 24. 10.1186/2041-9139-3-24
    1. Hall B. K. (2014). “Bones and Cartilage,” in Developmental and Evolutionary Skeletal Biology. Second Edition (Amsterdam: Elsevier/AP; ).
    1. Haub P., Meckel T. (2015). A Model Based Survey of Colour Deconvolution in Diagnostic Brightfield Microscopy: Error Estimation and Spectral Consideration. Sci. Rep. 5, 12096. 10.1038/srep12096
    1. Heuzé Y., Holmes G., Peter I., Richtsmeier J. T., Jabs E. W. (2014). Closing the gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses. Curr. Genet. Med. Rep. 2, 135–145. 10.1007/s40142-014-0042-x
    1. Holmes G., O'Rourke C., Perrine S. M. M., Lu N., van Bakel H., Richtsmeier J. T., et al. (2018). Midface and Upper Airway Dysgenesis in FGFR2-Craniosynostosis Involves Multiple Tissue-specific and Cell Cycle Effects. Development 145, dev166488. 10.1242/dev.166488
    1. Howie R. N., Herberg S., Durham E., Grey Z., Bennfors G., Elsalanty M., et al. (2018). Selective Serotonin Re-uptake Inhibitor Sertraline Inhibits Bone Healing in a Calvarial Defect Model. Int. J. Oral Sci. 10, 25. 10.1038/s41368-018-0026-x
    1. Huang W., Yang S., Shao J., Li Y.-P. (2007). Signaling and Transcriptional Regulation in Osteoblast Commitment and Differentiation. Front. Biosci. 12, 3068–3092. 10.2741/2296
    1. Ishizeki K., Saito H., Shinagawa T., Fujiwara N., Nawa T. (1999). Histochemical and Immunohistochemical Analysis of the Mechanism of Calcification of Meckel's Cartilage during Mandible Development in Rodents. J. Anat. 194 (Pt 2), 265–277. 10.1046/j.1469-7580.1999.19420265.x
    1. Ishizeki K., Takahashi N., Nawa T. (2001). Formation of the Sphenomandibular Ligament by Meckel's Cartilage in the Mouse: Possible Involvement of Epidermal Growth Factor as Revealed by Studies In Vivo and In Vitro . Cel Tissue Res. 304, 67–80. 10.1007/s004410100354
    1. Johnson D., Wilkie A. O. M. (2011). Craniosynostosis. Eur. J. Hum. Genet. 19, 369–376. 10.1038/ejhg.2010.235
    1. Kaucka M., Zikmund T., Tesarova M., Gyllborg D., Hellander A., Jaros J., et al. (2017). Oriented Clonal Cell Dynamics Enables Accurate Growth and Shaping of Vertebrate Cartilage. eLife 6, e25902. 10.7554/eLife.25902
    1. Khominsky A., Yong R., Ranjitkar S., Townsend G., Anderson P. J. (2018). Extensive Phenotyping of the Orofacial and Dental Complex in Crouzon Syndrome. Arch. Oral Biol. 86, 123–130. 10.1016/j.archoralbio.2017.10.022
    1. Kim J.-M., Yang Y.-S., Park K. H., Oh H., Greenblatt M. B., Shim J.-H. (2019). The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis. Ijms 20, 1803. 10.3390/ijms20081803
    1. Landini G., Martinelli G., Piccinini F. (2021). Colour Deconvolution: Stain Unmixing in Histological Imaging. Bioinformatics 37, 1485–1487. 10.1093/bioinformatics/btaa847
    1. Lee K. K. L., Peskett E., Quinn C. M., Aiello R., Adeeva L., Moulding D. A., et al. (2018). Overexpression of Fgfr2c Causes Craniofacial Bone Hypoplasia and Ameliorates Craniosynostosis in the Crouzon Mouse. Dis. Model. Mech. 11, dmm035311. 10.1242/dmm.035311
    1. Lele S., Richtsmeier J. T. (1995). Euclidean Distance Matrix Analysis: Confidence Intervals for Form and Growth Differences. Am. J. Phys. Anthropol. 98, 73–86. 10.1002/AJPA.1330980107
    1. Lele S. R., Richtsmeier J. T. (2001). An Invariant Approach to Statistical Analysis of Shapes. New York: Chapman and Hall/CRC. 10.1201/9781420036176
    1. Lesciotto K. M., Motch Perrine S. M., Kawasaki M., Stecko T., Ryan T. M., Kawasaki K., et al. (2020). Phosphotungstic Acid‐enhanced microCT: Optimized Protocols for Embryonic and Early Postnatal Mice. Dev. Dyn. 249, 573–585. 10.1002/dvdy.136
    1. Lesciotto K. M., Tomlinson L., Leonard S., Richtsmeier J. T. (2022). Embryonic and Early Postnatal Cranial Bone Volume and Tissue mineral Density Values for C57BL/6J Laboratory Mice. Dev. Dyn., 1–13. 10.1002/dvdy.458
    1. Lu X., Sawh-Martinez R., Forte A. J., Wu R., Cabrejo R., Wilson A., et al. (2019). Mandibular Spatial Reorientation and Morphological Alteration of Crouzon and Apert Syndrome. Ann. Plast. Surg. 83, 568–582. 10.1097/SAP.0000000000001811
    1. Lu X., Sawh-Martinez R., Forte A. J., Wu R., Cabrejo R., Wilson A., et al. (2020). Classification of Subtypes of Crouzon Syndrome Based on the Type of Vault Suture Synostosis. J. Craniofac. Surg. 31, 678–684. 10.1097/SCS.0000000000006173
    1. Manocha S., Farokhnia N., Khosropanah S., Bertol J. W., Santiago J., Fakhouri W. D. (2019). Systematic Review of Hormonal and Genetic Factors Involved in the Nonsyndromic Disorders of the Lower Jaw. Dev. Dyn. 248, 162–172. 10.1002/dvdy.8
    1. Martínez-Abadías N., Percival C., Aldridge K., Hill C. A., Ryan T., Sirivunnabood S., et al. (2010). Beyond the Closed Suture in Apert Syndrome Mouse Models: Evidence of Primary Effects of FGFR2 Signaling on Facial Shape at Birth. Dev. Dyn. 239, 3058–3071. 10.1002/dvdy.22414
    1. Martínez-Abadías N., Motch S. M., Pankratz T. L., Wang Y., Aldridge K., Jabs E. W., et al. (2013). Tissue-specific Responses to Aberrant FGF Signaling in Complex Head Phenotypes. Dev. Dyn. 242, 80–94. 10.1002/dvdy.23903
    1. Maruyama T., Mirando A. J., Deng C.-X., Hsu W. (2010). The Balance of WNT and FGF Signaling Influences Mesenchymal Stem Cell Fate during Skeletal Development. Sci. Signal. 3, ra40. 10.1126/scisignal.2000727
    1. McKenzie J. (1958). The First Arch Syndrome. Arch. Dis. Child. 33, 477–486. 10.1136/adc.33.171.477
    1. Miraoui H., Oudina K., Petite H., Tanimoto Y., Moriyama K., Marie P. J. (2009). Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling. J. Biol. Chem. 284, 4897–4904. 10.1074/jbc.M805432200
    1. Mori-Akiyama Y., Akiyama H., Rowitch D. H., de Crombrugghe B. (2003). Sox9 Is Required for Determination of the Chondrogenic Cell Lineage in the Cranial Neural Crest. Proc. Natl. Acad. Sci. U.S.A. 100, 9360–9365. 10.1073/pnas.1631288100
    1. Motch Perrine S. M., Stecko T., Neuberger T., Jabs E. W., Ryan T. M., Richtsmeier J. T. (2017). Integration of Brain and Skull in Prenatal Mouse Models of Apert and Crouzon Syndromes. Front. Hum. Neurosci. 11, 369. 10.3389/fnhum.2017.00369
    1. Motch Perrine S. M., Wu M., Stephens N. B., Kriti D., van Bakel H., Jabs E. W., et al. (2019). Mandibular Dysmorphology Due to Abnormal Embryonic Osteogenesis in FGFR2-Related Craniosynostosis Mice. Dis. Models Mech. 12, dmm038513. 10.1242/dmm.038513
    1. Motch Perrine S. M., Pitirri M. K., Durham E. L., Kawasaki M., Zheng H., Chen D. Z., et al. (2021). Over 400 Million Years of Cooperation: Untangling the Chondrocranium-Dermatocranium Connection. bioRxiv 2021.11.24.469914. 10.1101/2021.11.24.469914
    1. Musy M., Flaherty K., Raspopovic J., Robert-Moreno A., Richtsmeier J., Sharpe J. (2018). A Quantitative Method for Staging Mouse Embryos Based on Limb Morphometry. Development 145, dev154856. 10.1242/dev.154856
    1. Nakamura M., Yang M.-C., Ashida K., Mayanagi M., Sasano Y. (2021). Calcification and resorption of mouse Meckel's cartilage analyzed by von Kossa and tartrate-resistant acid phosphatase histochemistry and scanning electron microscopy/energy-dispersive X-ray spectrometry. Anat. Sci. Int. 97, 213–220. 10.1007/s12565-021-00643-6
    1. Ornitz D. M., Itoh N. (2015). The Fibroblast Growth Factor Signaling Pathway. WIREs Dev. Biol. 4, 215–266. 10.1002/wdev.176
    1. Parada C., Han D., Grimaldi A., Sarrión P., Park S. S., Pelikan R., et al. (2015). Disruption of the ERK/MAPK Pathway in Neural Crest Cells as a Potential Cause of Pierre Robin Sequence. Development 142, 3734–3745. 10.1242/dev.125328
    1. Perlyn C. A., Morriss-Kay G., Darvann T., Tenenbaum M., Ornitz D. M. (2006). Model for the Pharmacologic Treatment of Crouzon Syndrome. Neurosurgery 59, 210–215. 10.1227/01.NEU.0000224323.53866.1E
    1. Ramaesh T., Bard J. B. L. (2003). The Growth and Morphogenesis of the Early Mouse Mandible: A Quantitative Analysis. J. Anat. 203, 213–222. 10.1046/j.1469-7580.2003.00210.x
    1. Ray A. T., Mazot P., Brewer J. R., Catela C., Dinsmore C. J., Soriano P. (2020). FGF Signaling Regulates Development by Processes beyond Canonical Pathways. Genes Dev. 34, 1735–1752. 10.1101/gad.342956.120
    1. Ronneberger O., Fischer P., Brox T. (2015). “U-net: Convolutional Networks for Biomedical Image Segmentation,” in Medical Image Computing and Computer-Assisted Intervention – MICCAI 2015. Editors Navab N., Hornegger J., Wells W. M., Frangi A. F. (Cham: Springer International Publishing; ), 234–241. 10.1007/978-3-319-24574-4_28
    1. Ruifrok A. C., Johnston D. A. (2001). Quantification of Histochemical Staining by Color Deconvolution. Anal. Quant. Cytol. Histol. 23 (4), 291–299.
    1. Sakakura Y., Hosokawa Y., Tsuruga E., Irie K., Yajima T. (2007). In Situ localization of Gelatinolytic Activity during Development and Resorption of Meckel's Cartilage in Mice. Eur. J. Oral Sci. 115, 212–223. 10.1111/j.1600-0722.2007.00447.x
    1. Shibata S., Yokohama-Tamaki T. (2008). Anin Situhybridization Study ofRunx2,Osterix, andSox9in the Anlagen of Mouse Mandibular Condylar Cartilage in the Early Stages of Embryogenesis. J. Anat. 213, 274–283. 10.1111/j.1469-7580.2008.00934.x
    1. Shibata S., Sakamoto Y., Yokohama-Tamaki T., Murakami G., Cho B. H. (2014). Distribution of Matrix Proteins in Perichondrium and Periosteum during the Incorporation of Meckel's Cartilage into Ossifying Mandible in Midterm Human Fetuses: An Immunohistochemical Study. Anat. Rec. 297, 1208–1217. 10.1002/ar.22911
    1. Shone V., Oulion S., Casane D., Laurenti P., Graham A. (2016). Mode of Reduction in the Number of Pharyngeal Segments within the Sarcopterygians. Zoolog. Lett 2, 6. 10.1186/s40851-016-0043-6
    1. Svandova E., Anthwal N., Tucker A. S., Matalova E. (2020). Diverse Fate of an Enigmatic Structure: 200 Years of Meckel's Cartilage. Front. Cel Dev. Biol. 8, 821. 10.3389/fcell.2020.00821
    1. Wilsman N. J., Bernardini E. S., Leiferman E., Noonan K., Farnum C. E. (2008). Age and Pattern of the Onset of Differential Growth Among Growth Plates in Rats. J. Orthop. Res. 26, 1457–1465. 10.1002/jor.20547
    1. Xiao G., Jiang D., Thomas P., Benson M. D., Guan K., Karsenty G., et al. (2000). MAPK Pathways Activate and Phosphorylate the Osteoblast-specific Transcription Factor, Cbfa1. J. Biol. Chem. 275, 4453–4459. 10.1074/jbc.275.6.4453
    1. Xiao G., Jiang D., Gopalakrishnan R., Franceschi R. T. (2002). Fibroblast Growth Factor 2 Induction of the Osteocalcin Gene Requires MAPK Activity and Phosphorylation of the Osteoblast Transcription Factor, Cbfa1/Runx2. J. Biol. Chem. 277, 36181–36187. 10.1074/jbc.M206057200
    1. Xu W., Luo F., Wang Q., Tan Q., Huang J., Zhou S., et al. (2017). Inducible Activation of FGFR2 in Adult Mice Promotes Bone Formation after Bone Marrow Ablation. J. Bone Miner Res. 32, 2194–2206. 10.1002/jbmr.3204
    1. Yeh E., Atique R., Ishiy F. A. A., Fanganiello R. D., Alonso N., Matushita H., et al. (2012). FGFR2 Mutation Confers a Less Drastic Gain of Function in Mesenchymal Stem Cells Than in Fibroblasts. Stem Cel Rev Rep 8, 685–695. 10.1007/s12015-011-9327-6
    1. Yu K., Xu J., Liu Z., Sosic D., Shao J., Olson E. N., et al. (2003). Conditional Inactivation of FGF Receptor 2 Reveals an Essential Role for FGF Signaling in the Regulation of Osteoblast Function and Bone Growth. Development 130, 3063–3074. 10.1242/dev.00491
    1. Zheng H., Motch Perrine S. M., Pitirri M. K., Kawasaki K., Wang C., Richtsmeier J. T., et al. (2020). Cartilage Segmentation in High-Resolution 3D Micro-CT Images via Uncertainty-Guided Self-Training with Very Sparse Annotation. Med. Image Comput. Comput. Assist. Interv. 12261, 802–812. 10.1007/978-3-030-59710-8_78

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi