Integumentary System - Tooth Development

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The tooth is an extrordinary integumentary system specialization providing insights into epitheilal/mesenchymal (ectoderm of the first pharyngeal arch and neural crest, ectomesenchymal cells) interactions in development and has a major contribution from the neural crest. (More? Neural Crest Development)

There are 4 morphological stages describing the early tooth development: bud, cap, bell, and terminal differentiation.

lamina placode bud cap bell
lamina placode stage bud stage cap stage bell stage

Links: Gastrointestinal Tract Development

Integumentary Links: Introduction | Lecture | Hair | Tooth | Nail | Gland | Mammary Gland | Eyelid | Outer Ear | Touch | Histology | Abnormalities | Category:Integumentary
Historic Embryology
1910 Manual of Human Embryology | 1923 Head Subcutaneous Plexus | 1921 Text-Book of Embryology | Historic Disclaimer

Some Recent Findings

Neonatal rat teeth
  • Fate of HERS during tooth root development.[1] "Tooth root development begins after the completion of crown formation in mammals. Previous studies have shown that Hertwig's epithelial root sheath (HERS) plays an important role in root development, but the fate of HERS has remained unknown. In order to investigate the morphological fate and analyze the dynamic movement of HERS cells in vivo, we generated K14-Cre;R26R mice. HERS cells are detectable on the surface of the root throughout root formation and do not disappear. Most of the HERS cells are attached to the surface of the cementum, and others separate to become the epithelial rest of Malassez. HERS cells secrete extracellular matrix components onto the surface of the dentin before dental follicle cells penetrate the HERS network to contact dentin. HERS cells also participate in the cementum development and may differentiate into cementocytes. During root development, the HERS is not interrupted, and instead the HERS cells continue to communicate with each other through the network structure. Furthermore, HERS cells interact with cranial neural crest derived mesenchyme to guide root development. Taken together, the network of HERS cells is crucial for tooth root development."
  • Expression survey of genes critical for tooth development in the human embryonic tooth germ.[2] "examined the expression patterns of several regulatory genes, including BMP4, FGF8, MSX1, PAX9, PITX2, and SHOX2, and compared them with that found in mice. ...results indicate that, although slight differences exist in the gene expression patterns, the human and mouse teeth not only share considerable homology in odontogenesis but also use similar underlying molecular networks."
  • Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development[3] "Pax9 and Msx1 encode transcription factors that are known to be essential for the switch in odontogenic potential from the epithelium to the mesenchyme. ... Our findings demonstrate the partnership of Pax9 and Msx1 in a signaling pathway that involves Bmp4. Furthermore, the regulation of Bmp4 expression by the interaction of Pax9 with Msx1 at the level of transcription and through formation of a protein complex determines the fate of the transition from bud to cap stage during tooth development."
More recent papers
Mark Hill.jpg
This table shows an automated computer PubMed search using the listed sub-heading term.
  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: Tooth Embryology

Y D He, B D Sui, M Li, J Huang, S Chen, L A Wu Site-specific function and regulation of Osterix in tooth root formation. Int Endod J: 2015; PubMed 26599722

Vahe M Zohrabian, Colin S Poon, James J Abrahams Embryology and Anatomy of the Jaw and Dentition. Semin. Ultrasound CT MR: 2015, 36(5);397-406 PubMed 26589693

Mohsen Dalband, Iraj Amiri, Ali Reza Soltanian, Mehdi Gholami, Adell Khayati, Vahid Keshmirypor Comparing Viability of Periodontal Ligament Stem Cells Isolated From Erupted and Impacted Tooth Root. J Craniofac Surg: 2015, 26(7);e608-e612 PubMed 26468840

Claire Bardet, Frédéric Courson, Yong Wu, Mayssam Khaddam, Benjamin Salmon, Sandy Ribes, Julia Thumfart, Paulo M Yamaguti, Gael Y Rochefort, Marie-Lucile Figueres, Tilman Breiderhoff, Alejandro Garcia-Castaño, Benoit Vallée, Dominique Le Denmat, Brigitte Baroukh, Thomas Guilbert, Alain Schmitt, Jean-Marc Massé, Dominique Bazin, Georg Lorenz, Maria Morawietz, Jianghui Hou, Patricia Carvalho-Lobato, Maria Cristina Manzanares, Jean-Christophe Fricain, Deborah Talmud, Renato Demontis, Francisco Neves, Delphine Zenaty, Ariane Berdal, Andreas Kiesow, Matthias Petzold, Suzanne Menashi, Agnes Linglart, Ana Carolina Acevedo, Rosa Vargas-Poussou, Dominik Muller, Pascal Houillier, Catherine Chaussain Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation. J. Bone Miner. Res.: 2015; PubMed 26426912

Moacir Guilherme da Costa, Camilo Aquino Melgaço, Patrícia Corrêa-Faria, Leandro Silva Marques Functional and Esthetic Treatment of Lateral Incisor Agenesis with a Mini-Implant in a Young Patient: A Case Report. Int J Orthod Milwaukee: 2015, 26(2);55-7 PubMed 26349292


  • Human Embryology (2nd ed.) Larson Chapter 14 p443-455
  • The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Chapter 20: P513-529
  • Before We Are Born (5th ed.) Moore and Persaud Chapter 21: P481-496
  • Essentials of Human Embryology Larson Chapter 14: P303-315
  • Human Embryology, Fitzgerald and Fitzgerald
  • Color Atlas of Clinical Embryology Moore Persaud and Shiota Chapter 15: p231-236

Development Overview

  • ectoderm, mesoderm and neural crest ectomesenchyme contribute
  • inductive influence of neural crest with overlying ectoderm


  • neural crest-derived mesenchymal cells
  • differentiate under the influence of the enamel epithelium
  • form predentin
  • calcifies to form dentin


  • produce enamal
  • tooth growth occurs in ossifying jaws
  • periodontal ligament holds tooth in bone socket

Tooth Stages

Tooth development stages[4]
Human (weeks) Mouse (days)
lamina lamina Week 6 E11
placode placode stage Week 7 E11.5
bud bud stage Week 8 E12.5
cap cap stage Week 11 E14.5
bell bell stage Week 14 E15.5

Images: all stages | lamina | placode stage | bud stage | cap stage | bell stage

Human 2 Sets of Teeth

Human permanent teeth appearance (eruption)

Human Dentition Timeline

The milk dentition
Median incisors 6th to 8th month
Lateral incisors 8th to 12th month
First molars 12th to 16th month
Canines 1 7th to 20th month
Second molars 20th to 24th month
The permanent dentition
First molars 7th year
Median incisors 8th year
Lateral incisors 9th year
First premolars 10th year
Second premolars 11th year
Canines 13th to 14th year
Second molars 13th to 14th year
Third molars 17th to 40th year
Source: The Teeth (1912)[5]

Deciduous Teeth

  • 20 deciduous teeth
  • Differential rates of growth, shed at different times over 20 year period

Deciduous teeth

Permanent Teeth

Human adult mandibular teeth pattern
  • 32 permanent teeth
  • Incisors - sharp cutting edge, adapted for biting the food.
  • Canines - are larger and stronger than the incisors. The upper canines have also been called the "eye teeth", while the lower canines "stomach teeth".
  • Premolars - or Bicuspid teeth are smaller and shorter than the canines.
  • Molars - are the largest teeth adapted for grinding and pounding food.

Permanent teeth

Epithelial Mesenchymal Interaction

local ectodermal thickening expresses several signaling molecules these in turn signal to the underlying mesenchyme triggering mesenchymal condensation (epithelially expressed Bmp4 induces Msx1 and Lef1 as well as itself in the underlying mesenchyme)

Four epithelial signaling molecules, Bmp2, Shh, Wnt10a, and Wnt10b, in the early inductive cascade, each signal has a distinct molecular action on the jaw mesenchyme.

Mouse (E11.0 and E12.0) - all four genes are specifically expressed in the epithelium.

Shh and Wnt10b induce general Hedgehog and Wnt targets, Ptc and Gli for Shh and Lef1 for Wnt10b,

Bmp2 is able to induce tooth-specific expression of Msx1.

(Text above modified from: Hélène R. Dassule and Andrew P. McMahon Developmental Biology, v 202, n 2, October 15, 1998, p215-227)

(More? Developmental Mechanism - Epithelial Mesenchymal Interaction)

Periodontal Ligament

The tooth is not anchored directly onto its bony socket (alveolar bone) but held in place by the periodontal ligament (PDL), a specialized connective tissue structure that surrounds the tooth root coating of cementum.

The additional roles of the PDL are to also act as; a shock absorber, transmitter of chewing forces (from tooth to bone), sensory information (heat, cold, pressure and pain).

The collagen fiber bundles within the ligament are called "Sharpey’s fibres".

Cementum (from investing layer of the dental follicle) is contiguous layer with the periodontal ligament on one surface and firmly adherent to dentine on the other surface.

Molecular Tooth Development

Tooth molecular development[4]

More than 300 genes have been associated with tooth development including: BMP4, FGF8, MSX1, MSX2, PAX9, PITX2, SHOX2, Delta/Notch, Hox-8, Runx2

Most recent review in Developmental Dynamics by Lin D, Huang Y, He F, Gu S, Zhang G, Chen Y, Zhang Y. Expression survey of genes critical for tooth development in the human embryonic tooth germ. Dev Dyn. 2007 Mar 29.

Amelogenin - abundant protein secreted by ameloblasts which is a major component of tooth enamel.

The papers below are from UNSW Embryology (version 3), information requires updating.

Bone Morphogenic Protein (BMP) / Fibroblast Growth Factor (FGF)

Growth factors in the BMP- and FGF-families are expressed in dental epithelium during initiation of tooth development and their effects on the underlying mesenchyme mimic those of the epithelium. They upregulate the expression of many genes, including the homeobox-containing Msx-1 and Msx-2, and stimulate cell proliferation suggesting that they may act as epithelial signals transmitting epithelial-mesenchymal interactions. During subsequent morphogenesis, when the characteristic shapes of individual teeth develop as a result from folding of the dental epithelium, several signal molecules including Sonic hedgehog, Bmps-2, 4, 7 and Fgf-4 are expressed specifically in restricted and transient epithelial cell clusters, called enamel knots.

(Text: Irma Thesleff and Carin Sahlberg Seminars in Cell & Developmental Biology, v 7, n 2, April, 1996, p185-193)


The expression pattern of Delta 1 in ameloblasts and odontoblasts is complementary to Notch1, Notch2, and Notch3 expression in adjacent epithelial and mesenchymal cells. Notch1 and Notch2 are upregulated in explants of dental mesenchyme adjacent to implanted cells expressing Delta1, suggesting that feedback regulation by Delta-Notch signaling ensures the spatial segregation of Notch receptors and ligands. TGF1 and BMPs induce Delta1 expression in dental mesenchyme explants at the stage at which Delta1 is upregulated in vivo, but not at earlier stages. In contrast to the Notch family receptors and their ligand Jagged1, expression of Delta1 in the tooth germ is not affected by epithelial-mesenchymal interactions, showing that the Notch receptors and their two ligands Jagged1 and Delta1 are subject to different regulations.

Text: Mitsiadis etal Developmental Biology,v 204, n 2, December 15, 1998, p420-431


Inherited dentine disorders[6]


A total lack of tooth development.

Dentinogenesis imperfecta

The teeth are translucent and often roughened with severe amber discolouration. Discoloured teeth with an opalescent sheen, dentin does not support enamel (dentin sialophosphoprotein mutation)

Dentine dysplasia

The primary teeth are translucent and amber in colour whereas the erupting secondary central incisors are of normal appearance.

Amelogenesis Imperfecta

Abnormal tooth enamel formation (AMELX, ENAM, KLK4, MMP20).

Dens Evaginatus

Dental anomaly mainly affecting premolars in people of Mongolian origin.


Lack of development of one or more teeth.

Hypohidrotic Ectodermal Dysplasia

Maldevelopment of one or more ectodermal-derived tissues.


Small teeth.

Hutchinson's teeth

(Hutchinson's incisor, Hutchinson's sign, Hutchinson-Boeck teeth) Historic clinical term for an infant tooth abnormality associated with congenital syphilis. Teeth are smaller, more widely spaced than normal and have notches on the biting surfaces. Named after Jonathan Hutchinson (1828 – 1913) an English surgeon and pathologist, who first described this association.

Links: Abnormal Development - Syphilis


  1. Xiaofeng Huang, Pablo Bringas, Harold C Slavkin, Yang Chai Fate of HERS during tooth root development. Dev. Biol.: 2009, 334(1);22-30 PubMed 19576204
  2. Dahe Lin, Yide Huang, Fenglei He, Shuping Gu, Guozhong Zhang, YiPing Chen, Yanding Zhang Expression survey of genes critical for tooth development in the human embryonic tooth germ. Dev. Dyn.: 2007, 236(5);1307-12 PubMed 17394220
  3. Takuya Ogawa, Hitesh Kapadia, Jian Q Feng, Rajendra Raghow, Heiko Peters, Rena N D'Souza Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. J. Biol. Chem.: 2006, 281(27);18363-9 PubMed 16651263
  4. 4.0 4.1 Despina S Koussoulakou, Lukas H Margaritis, Stauros L Koussoulakos A curriculum vitae of teeth: evolution, generation, regeneration. Int. J. Biol. Sci.: 2009, 5(3);226-43 PubMed 19266065 | PMCID: PMC2651620
  5. Manual of Human Embryology II Keibel, F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)
  6. Martin J Barron, Sinead T McDonnell, Iain Mackie, Michael J Dixon Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia. Orphanet J Rare Dis: 2008, 3;31 PubMed 19021896



R Peterkova, M Hovorakova, M Peterka, H Lesot Three-dimensional analysis of the early development of the dentition. Aust Dent J: 2014, 59 Suppl 1;55-80 PubMed 24495023

Marianna Bei Molecular genetics of tooth development. Curr. Opin. Genet. Dev.: 2009, 19(5);504-10 PubMed 19875280

Maisa Seppala, Maria Zoupa, Obinna Onyekwelu, Martyn T Cobourne Tooth development: 1. Generating teeth in the embryo. Dent Update: 2006, 33(10);582-4, 586-8, 590-1 PubMed 17209531

Irma Thesleff The genetic basis of tooth development and dental defects. Am. J. Med. Genet. A: 2006, 140(23);2530-5 PubMed 16838332

Kevin Tompkins Molecular mechanisms of cytodifferentiation in mammalian tooth development. Connect. Tissue Res.: 2006, 47(3);111-8 PubMed 16753804

Martyn T Cobourne, Paul T Sharpe Tooth and jaw: molecular mechanisms of patterning in the first branchial arch. Arch. Oral Biol.: 2003, 48(1);1-14 PubMed 12615136

P T Sharpe Neural crest and tooth morphogenesis. Adv. Dent. Res.: 2001, 15;4-7 PubMed 12640730


Dahe Lin, Yide Huang, Fenglei He, Shuping Gu, Guozhong Zhang, YiPing Chen, Yanding Zhang Expression survey of genes critical for tooth development in the human embryonic tooth germ. Dev. Dyn.: 2007, 236(5);1307-12 PubMed 17394220

M Nakatomi, I Morita, K Eto, M S Ota Sonic hedgehog signaling is important in tooth root development. J. Dent. Res.: 2006, 85(5);427-31 PubMed 16632755

Takuya Ogawa, Hitesh Kapadia, Jian Q Feng, Rajendra Raghow, Heiko Peters, Rena N D'Souza Functional consequences of interactions between Pax9 and Msx1 genes in normal and abnormal tooth development. J. Biol. Chem.: 2006, 281(27);18363-9 PubMed 16651263

P Kettunen, I Thesleff Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis. Dev. Dyn.: 1998, 211(3);256-68 PubMed 9520113

Search PubMed

Search Pubmed: Tooth Development | odontogenesis | tooth morphogenesis | adontia | amelogenesis imperfecta | dens evaginatus | hypodontia

Additional Images

Category:Tooth | Category:Integumentary


Development and Morphology of the Teeth (1902)

The Teeth (1912)

The Teeth (1921)


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Cite this page: Hill, M.A. (2015) Embryology Integumentary System - Tooth Development. Retrieved November 26, 2015, from

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