Msx2 Prevents Stratified Squamous Epithelium Formation in the Enamel Organ

Author:

Nakatomi M.12,Ida-Yonemochi H.1,Nakatomi C.34,Saito K.1,Kenmotsu S.1,Maas R.L.5,Ohshima H.1

Affiliation:

1. Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

2. Division of Anatomy, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan

3. General Dentistry and Clinical Education Unit, Niigata University Medical and Dental Hospital, Niigata, Japan

4. Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan

5. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Abstract

Tooth enamel is manufactured by the inner enamel epithelium of the multilayered enamel organ. Msx2 loss-of-function mutation in a mouse model causes an abnormal accumulation of epithelial cells in the enamel organ, but the underlying mechanism by which Msx2 regulates amelogenesis is poorly understood. We therefore performed detailed histological and molecular analyses of Msx2 null mice. Msx2 null ameloblasts and stratum intermedium (SI) cells differentiated normally in the early stages of amelogenesis. However, during subsequent developmental stages, the outer enamel epithelium (OEE) became highly proliferative and transformed into a keratinized stratified squamous epithelium that ectopically expressed stratified squamous epithelium markers, including Heat shock protein 25, Loricrin, and Keratin 10. Moreover, expression of hair follicle–specific keratin genes such as Keratin 26 and Keratin 73 was upregulated in the enamel organ of Msx2 mutants. With the accumulation of keratin in the stellate reticulum (SR) region and subsequent odontogenic cyst formation, SI cells gradually lost the ability to differentiate, and the expression of Sox2 and Notch1 was downregulated, leading to ameloblast depolarization. As a consequence, the organization of the Msx2 mutant enamel organ became disturbed and enamel failed to form in the normal location. Instead, there was ectopic mineralization that likely occurred within the SR. In summary, we show that during amelogenesis, Msx2 executes a bipartite function, repressing the transformation of OEE into a keratinized stratified squamous epithelium while simultaneously promoting the development of a properly differentiated enamel organ competent for enamel formation.

Funder

Foundation for the National Institutes of Health

the Japan Society for the Promotion of Science KAKENHI

Publisher

SAGE Publications

Subject

General Dentistry

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