Skip to main content
SpringerLink
Log in

Augmented Indian hedgehog signaling in cranial neural crest cells leads to craniofacial abnormalities and dysplastic temporomandibular joint in mice

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Extensive studies have pinpointed the crucial role of Indian hedgehog (Ihh) signaling in the development of the appendicular skeleton and the essential function of Ihh in the formation of the temporomandibular joint (TMJ). In this study, we have investigated the effect of augmented Ihh signaling in TMJ development. We took a transgenic gain-of-function approach by overexpressing Ihh in the cranial neural crest (CNC) cells using a conditional Ihh transgenic allele and the Wnt1-Cre allele. We found that Wnt1-Cre-mediated tissue-specific overexpression of Ihh in the CNC lineage caused severe craniofacial abnormalities, including cleft lip/palate, encephalocele, anophthalmos, micrognathia, and defective TMJ development. In the mutant TMJ, the glenoid fossa was completely absent, whereas the condyle and the articular disc appeared relatively normal with slightly delayed chondrocyte differentiation. Our findings thus demonstrate that augmented Ihh signaling is detrimental to craniofacial development, and that finely tuned Ihh signaling is critical for TMJ formation. Our results also provide additional evidence that the development of the condyle and articular disc is independent of the glenoid fossa.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Beresford WA (1975) Schemes of zonation in the mandibular condyle. Am J Orthod 68:189–195

    Article  CAS  PubMed  Google Scholar 

  • Chai Y, Jiang X, Ito Y, Bringas PJ, Han J, Rowitch DH, Soriano P, McMahon AP, Sucov HM (2000) Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127:1671–1679

    CAS  PubMed  Google Scholar 

  • Chen J, Utreja A, Kalajzic Z, Sobue T, Rowe D, Wadhwa S (2012) Isolation and characterization of murine mandibular condylar cartilage cell populations. Cells Tissues Organs 195:232–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407–413

    Article  CAS  PubMed  Google Scholar 

  • Chow RL, Lang RA (2001) Early eye development in vertebrates. Annu Rev Cell Dev Biol 17:255–296

    Article  CAS  PubMed  Google Scholar 

  • Danielian PS, Muccino D, Rowitch DH, Michael SK, McMahon AP (1998) Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol 8:1323–1326

    Article  CAS  PubMed  Google Scholar 

  • Frommer J (1964) Prenatal development of the mandibular joint in mice. Anat Rec 150:449–461

    Article  CAS  PubMed  Google Scholar 

  • Fukuoka H, Shibata S, Suda N, Yamashita Y, Komori T (2007) Bone morphogenetic protein rescues the lack of secondary cartilage in Runx2-deficient mice. J Anat 211:8–15

    Article  PubMed  PubMed Central  Google Scholar 

  • Gu S, Chen Y (2013) Temporomandibular joint development. In: Huang GT-J, Thesleff I (eds) Stem cells in craniofacial development and regeneration. Wiley-Blackwell, New York, pp 71–85

    Chapter  Google Scholar 

  • Gu S, Wei N, Yu L, Fei J, Chen Y (2008) Shox2-deficiency leads to dysplasia and ankylosis of the temporomandibular joint in mice. Mech Dev 125:729–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu S, Wu W, Liu C, Yang L, Sun C, Ye W, Li X, Chen J, Long F, Chen Y (2014) BMPRIA mediated signaling is essential for temporomandibular joint development in mice. PLoS One 9:e101000

    Article  PubMed  PubMed Central  Google Scholar 

  • He F, Xiong W, Wang Y, Matsui M, Yu X, Chai Y, Klingensmith J, Chen Y (2010) Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis. Dev Biol 347:109–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087

    Article  CAS  PubMed  Google Scholar 

  • Jiang X, Iseki S, Maxson RE, Sucov HM, Morriss-Kay GM (2002) Tissue origins and interactions in the mammalian skull vault. Dev Biol 241:106–116

    Article  CAS  PubMed  Google Scholar 

  • Kantomaa T, Tuominen M, Pirttiniemi P (1994) Effect of mechanical forces on chondrocyte maturation and differentiation in the mandibular condyle of the rat. J Dent Res 73:1150–1156

    CAS  PubMed  Google Scholar 

  • Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LH, Ho C, Mulligan RC, Abou-Samra AB, Jüppner H, Segre GV, Kronenberg HM (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:663–666

    Article  CAS  PubMed  Google Scholar 

  • Li X, Liu H, Gu S, Liu C, Sun C, Zheng Y, Chen Y (2014) Replacing Shox2 with human SHOX leads to congenital disc degeneration of the temporomandibular joint in mice. Cell Tissue Res 355:345–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luder HU, Leblond CP, Mark K von der (1988) Cellular stages in cartilage formation as revealed by morphometry, radioautography and type II collagen immunostaining of the mandibular condyle from weanling rats. Am J Anat 182:197–214

  • Mori-Akiyama Y, Akiyama H, Rowitch DH, Crombrugghe B de (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

  • Ochiai T, Shibukawa Y, Nagayama M, Mundy C, Yasuda T, Okabe T, Shimono K, Kanyama M, Hasegawa H, Maeda Y, Lanske B, Pacifici M, Koyama E (2010) Indian hedgehog roles in post-natal TMJ development and organization. J Dent Res 89:349–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oka K, Oka S, Sasaki T, Ito Y, Bringas PJ, Nonaka K, Chai Y (2007) The role of TGF-beta signaling in regulating chondrogenesis and osteogenesis during mandibular development. Dev Biol 303:391–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osumi-Yamashita N, Ninomiya Y, Doi H, Eto K (1994) The contribution of both forebrain and midbrain crest cells to the mesenchyme in the frontonasal mass of mouse embryos. Dev Biol 164:409–419

    Article  CAS  PubMed  Google Scholar 

  • Presnell J, Schreibman M (1997) Humason’s animal tissue techniques, 5th edn. The Johns Hopkins University Press, Baltimore

    Google Scholar 

  • Purcell P, Joo BW, Hu JK, Tran PV, Calicchio ML, O’Connell DJ, Maas RL, Tabin CJ (2009) Temporomandibular joint formation requires two distinct hedgehog-dependent steps. Proc Natl Acad Sci U S A 106:18297–18302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Purcell P, Jheon A, Vivero MP, Rahimi H, Joo A, Klein OD (2012) Spry1 and spry2 are essential for development of the temporomandibular joint. J Dent Res 91:387–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rice DP (2008) Developmental anatomy of craniofacial sutures. Front Oral Biol 12:1–21

    Article  PubMed  Google Scholar 

  • Shibata S, Yokohama-Tamaki T (2008) An in situ hybridization study of Runx2, Osterix, and Sox9 in the anlagen of mouse mandibular condylar cartilage in the early stages of embryogenesis. J Anat 213:274–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata S, Suda N, Yoda S, Fukuoka H, Ohyama K, Yamashita Y, Komori T (2004) Runx2-deficient mice lack mandibular condylar cartilage and have deformed Meckel’s cartilage. Anat Embryol (Berl) 208:273–280

    Article  CAS  Google Scholar 

  • Shibukawa Y, Young B, Wu C, Yamada S, Long F, Pacifici M, Koyama E (2007) Temporomandibular joint formation and condyle growth require Indian hedgehog signaling. Dev Dyn 236:426–434

    Article  CAS  PubMed  Google Scholar 

  • Silbermann M, Frommer J (1972) The nature of endochondral ossification in the mandibular condyle of the mouse. Anat Rec 172:659–667

    Article  CAS  PubMed  Google Scholar 

  • Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21:70–71

    Article  CAS  PubMed  Google Scholar 

  • Sperber G (2001) Craniofacial development. Decker, Hamilton

    Google Scholar 

  • St Amand T, Zhang Y, Semina EV, Zhao X, Hu Y, Nguyen L, Murray JC, Chen Y (2000) Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. Dev Biol 217:323–332

    Article  CAS  PubMed  Google Scholar 

  • St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13:2072–2086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trainor PA, Tam PP (1995) Cranial paraxial mesoderm and neural crest cells of the mouse embryo: co-distribution in the craniofacial mesenchyme but distinct segregation in branchial arches. Development 121:2569–2582

    CAS  PubMed  Google Scholar 

  • Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273:613–622

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liu C, Rohr J, Liu H, He F, Yu J, Sun C, Li L, Gu S, Chen Y (2011) Tissue interaction is required for glenoid fossa development during temporomandibular joint formation. Dev Dyn 240:2466–2473

    Article  PubMed  PubMed Central  Google Scholar 

  • Xiong W, He F, Morikawa Y, Yu X, Zhang Z, Lan Y, Jiang R, Cserjesi P, Chen Y (2009) Hand2 is required in the epithelium for palatogenesis in mice. Dev Biol 330:131–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasuda T, Mundy C, Kinumatsu T, Shibukawa Y, Shibutani T, Grobe K, Minugh-Purvis N, Pacifici M, Koyama E (2010) Sulfotransferase Ndst1 is needed for mandibular and TMJ development. J Dent Res 89:1111–1116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Yu X, Zhang Y, Geronimo B, Lovlie A, Fromm SH, Chen Y (2000) Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limb. Dev Biol 220:154–167

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China

    Ling Yang

  2. Department of Cell and Molecular Biology, Tulane University, New Orleans, LA7 0118, USA

    Ling Yang, Shuping Gu, Wenduo Ye, Yingnan Song & YiPing Chen

  3. Southern Center for Biomedical Research, Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian, 350108, China

    Yingnan Song & YiPing Chen

Authors
  1. Ling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuping Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenduo Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yingnan Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. YiPing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ling Yang or YiPing Chen.

Ethics declarations

Disclosure statement

The authors declare no conflicts of interests pertaining to this article.

Additional information

This work was supported by the NIHR01 DE17792 (to Y.C.). L.Y. was supported by a fellowship from the China Scholarship Council (no. 201208440191).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Gu, S., Ye, W. et al. Augmented Indian hedgehog signaling in cranial neural crest cells leads to craniofacial abnormalities and dysplastic temporomandibular joint in mice. Cell Tissue Res 364, 105–115 (2016). https://doi.org/10.1007/s00441-015-2306-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-015-2306-5

Keywords

Search

Navigation