Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Meckel’s cartilage breakdown offers clues to mammalian middle ear evolution


A key transformation in mammalian ear evolution was incorporation of the primary jaw joint of premammalian synapsids into the definitive mammalian middle ear of living mammals. This evolutionary transition occurred in two steps, starting with a partial or ‘transitional’ mammalian middle ear in which the ectotympanic and malleus were still connected to the mandible by an ossified Meckel’s cartilage (MC), as observed in many Mesozoic mammals. This was followed by MC breakdown, freeing the ectotympanic and the malleus from the mandible and creating the definitive mammalian middle ear. Here we report new findings on the role of chondroclasts in MC breakdown, shedding light on how therian mammals lost the part of the MC connecting the ear to the jaw. Genetic or pharmacological loss of clast cells in mice and opossums leads to persistence of embryonic MC beyond juvenile stages, with MC ossification in mutant mice. The persistent MC causes a distinctive groove on the postnatal mouse dentary. This morphology phenocopies the ossified MC and Meckelian groove observed in Mesozoic mammals. Clast cell recruitment to MC is not observed in reptiles, where MC persists as a cartilaginous structure. We hypothesize that ossification of MC is an ancestral feature of mammaliaforms, and that a shift in the timing of clast cell recruitment to MC prior to its ossification is a key developmental mechanism for the evolution of the definitive mammalian middle ear in extant therians.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: c-Fos mutant mice mimic morphologies of PMME (‘TMME’) in fossil mammaliaforms.
Figure 2: Detachment of the malleus in mammals is due to recruitment of c-Fos-dependent chondroclasts.
Figure 3: Formation of Meckelian groove as evidence for presence of retained MC in mammaliaforms.
Figure 4: Clast cell inhibition in the opossum Monodelphis domestica.


  1. Allin, E. F. & Hopson, J. A. in The Evolutionary Biology of Hearing (eds Webster, D. B., Fay, R. R. & Popper, A. N. ) 587–614 (Springer, 1992).

    Book  Google Scholar 

  2. Rowe, T. Coevolution of the mammalian middle ear and neocortex. Science 273, 651–654 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Luo, Z.-X. Transformation and diversification in early mammal evolution. Nature 450, 1011–1019 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Anthwal, N. & Tucker, A. S. in From Clone to Bone: The Synergy of Morphological and Molecular Tools in Palaeobiology (eds Asher, R. J. & Müller, J. ) 207–229 (Cambridge Univ. Press, 2012).

    Book  Google Scholar 

  5. Maier, W. & Ruf, I. Evolution of the mammalian middle ear: a historical review. J. Anat. 228, 270–283 (2016).

    Article  PubMed  Google Scholar 

  6. Luo, Z.-X. Developmental patterns in Mesozoic evolution of mammal ears. Annu. Rev. Ecol. Evol. Syst. 42, 355–380 (2011).

    Article  Google Scholar 

  7. Meng, J., Hu, Y., Wang, Y. & Li, C. The ossified Meckel’s cartilage and internal groove in Mesozoic mammaliaforms: implications to origin of the definitive mammalian middle ear. Zool. J. Linn. Soc. 138, 431–448 (2003).

    Article  Google Scholar 

  8. Ji, Q., Luo, Z.-X., Zhang, X., Yuan, C.-X. & Xu, L. Evolutionary development of the middle ear in Mesozoic therian mammals. Science 326, 278–281 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Takechi, M. & Kuratani, S. History of studies on mammalian middle ear evolution: a comparative morphological and developmental biology perspective. J. Exp. Zool. B 314, 417–433 (2010).

    Article  Google Scholar 

  10. Amano, O. et al. Meckel’s cartilage: discovery, embryology and evolution. J. Oral Biosci. 52, 125–135 (2010).

    Google Scholar 

  11. Anthwal, N., Joshi, L. & Tucker, A. S. Evolution of the mammalian middle ear and jaw: adaptations and novel structures. J. Anat. 222, 147–160 (2013).

    Article  PubMed  Google Scholar 

  12. Sánchez-Villagra, M. R., Gemballa, S., Nummela, S., Smith, K. K. & Maier, W. Ontogenetic and phylogenetic transformations of the ear ossicles in marsupial mammals. J. Morphol. 251, 219–238 (2002).

    Article  PubMed  Google Scholar 

  13. Amin, S. & Tucker, A. S. Joint formation in the middle ear: lessons from the mouse and guinea pig. Dev. Dyn. 235, 1326–1333 (2006).

    Article  PubMed  Google Scholar 

  14. Wilson, J. & Tucker, A. S. Fgf and Bmp signals repress the expression of Bapx1 in the mandibular mesenchyme and control the position of the developing jaw joint. Dev. Biol. 266, 138–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Meng, J., Wang, Y. & Li, C. Transitional mammalian middle ear from a new Cretaceous Jehol eutriconodont. Nature 472, 181–185 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Luo, Z.-X., Gatesy, S. M., Jenkins, F. A., Amaral, W. W. & Shubin, N. H. Mandibular and dental characteristics of Late Triassic mammaliaform Haramiyavia and their ramifications for basal mammal evolution. Proc. Natl Acad. Sci. USA 112, E7101–E7109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Holliday, C. M. & Nesbitt, S. J. Morphology and diversity of the mandibular symphysis of archosauriforms. Geol. Soc. Lond. Spec. Publ. 379, 555–571 (2013).

    Google Scholar 

  18. Smith, K. K. Craniofacial development in marsupial mammals: developmental origins of evolutionary change. Dev. Dyn. 235, 1181–1193 (2006).

    Article  PubMed  Google Scholar 

  19. Gaupp, E. W. T. Die Reichertsche theorie: (Hammer-, amboss-und kieferfrage). Arch. Anat. Suppl. 1912, 1–416 (1913).

  20. Hall, B. K. Bones and Cartilage: Developmental and Evolutionary Skeletal Biology. (Academic, 2015).

    Google Scholar 

  21. Knowles, H. J. et al. Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption. Virchows Arch. 461, 205–210 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Lewinson, D. & Silbermann, M. Chondroclasts and endothelial cells collaborate in the process of cartilage resorption. Anat. Rec. 233, 504–514 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Grigoriadis, A. et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443–448 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Arai, A. et al. Fos plays an essential role in the upregulation of RANK expression in osteoclast precursors within the bone microenvironment. J. Cell Sci. 125, 2910–2917 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Rogers, M. J., Crockett, J. C., Coxon, F. P. & Mönkkönen, J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone 49, 34–41 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Martin, T. et al. A Cretaceous eutriconodont and integument evolution in early mammals. Nature 526, 380–384 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Raff, R. A. Written in stone: fossils, genes and evo–devo. Nat. Rev. Genet. 8, 911–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Urban, D. J. U. et al. A new developmental mechanism for the separation of the mammalian middle ear ossicles from the jaw. Proc. R. Soc. B. (in the press).

  29. Sakakura, Y. Role of matrix metalloproteinases in extracellular matrix disintegration of Meckel’s cartilage in mice. J. Oral Biosci. 52, 143–149 (2010).

    CAS  Google Scholar 

  30. Yang, L., Tsang, K. Y., Tang, H. C., Chan, D. & Cheah, K. S. E. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc. Natl Acad. Sci. USA 111, 12097–12102 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Boyce, B. F. et al. New roles for osteoclasts in bone. Ann. NY Acad. Sci. 1116, 245–254 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Sakakura, Y. et al. Immunolocalization of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in Meckel’s cartilage compared with developing endochondral bones in mice. J. Anat. 207, 325–337 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, Y., Zheng, Y., Chen, D. & Chen, Y. Enhanced BMP signaling prevents degeneration and leads to endochondral ossification of Meckel′s cartilage in mice. Dev. Biol. 381, 301–311 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Abzhanov, A. von Baer’s law for the ages: lost and found principles of developmental evolution. Trends Genet. 29, 712–722 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, Z. Q. et al. Bone and haematopoietic defects in mice lacking c-fos. Nature 360, 741–745 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Popa, E. M., Anthwal, N. & Tucker, A. S. Complex patterns of tooth replacement revealed in the fruit bat (Eidolon helvum). J. Anat. (2016). E-pub ahead of print.

  37. Ealba, E. L. et al. Neural crest-mediated bone resorption is a determinant of species-specific jaw length. Dev. Biol. 408, 151–163 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank C. Healy (KCL) and L. Yin (UIUC) for support with μCT, E. Popa (King’s College London, KCL) for assistance in processing tissue, J. M. Fons (KCL) for injection of newborn mice, A. Neander (University of Chicago) for graphics assistance, A. Grigoriadis (KCL) for supplying the c-Fos mutant mice and in situ probes, and J. Turner and F. Decarpentrie (Francis Crick Institute) for supplying opossum pups. For this project, N.A. was supported by the Leverhulme Trust (RPG-2013-070) and the Wellcome Trust (102889/Z/13/Z) and NSF/EDEN Research Exchange Grant (IOS 0955517) A.S.T. is funded by the Wellcome Trust (102889/Z/13/Z). D.J.U. was supported by a NSF Graduate Research Fellowship (2013136301) and K.E.S. by a Doctoral Dissertation Improvement Grant (1406802).

Author information

Authors and Affiliations



N.A. and A.S.T. conceived and designed the project. N.A. carried out mouse and reptile experimental work; K.E.S. and D.J.U. carried out opossum experimental work. Z.X.L. carried out fossil analysis. N.A. wrote the manuscript with A.S.T. A.S.T., Z.X.L, K.E.S. and D.J.U. critically appraised and edited the manuscript. All authors read and approved the manuscript before submission.

Corresponding author

Correspondence to Abigail S. Tucker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures 1–6; Supplementary Discussion (PDF 8546 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Anthwal, N., Urban, D., Luo, ZX. et al. Meckel’s cartilage breakdown offers clues to mammalian middle ear evolution. Nat Ecol Evol 1, 0093 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing