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Comparative Study
. 2013 Apr;140(7):1424-32.
doi: 10.1242/dev.089599. Epub 2013 Mar 5.

Sox2 Marks Epithelial Competence to Generate Teeth in Mammals and Reptiles

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Free PMC article
Comparative Study

Sox2 Marks Epithelial Competence to Generate Teeth in Mammals and Reptiles

Emma Juuri et al. Development. .
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Abstract

Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of successional tooth formation: tooth replacement and serial addition of primary teeth. We observed specific Sox2 expression in the dental lamina that gives rise to successional teeth in mammals with one round of tooth replacement as well as in reptiles with continuous tooth replacement. Sox2 was also expressed in the dental lamina during serial addition of mammalian molars, and genetic lineage tracing indicated that Sox2(+) cells of the first molar give rise to the epithelial cell lineages of the second and third molars. Moreover, conditional deletion of Sox2 resulted in hyperplastic epithelium in the forming posterior molars. Our results indicate that the Sox2(+) dental epithelium has competence for successional tooth formation and that Sox2 regulates the progenitor state of dental epithelial cells. The findings imply that the function of Sox2 has been conserved during evolution and that tooth replacement and serial addition of primary teeth represent variations of the same developmental process. The expression patterns of Sox2 support the hypothesis that dormant capacity for continuous tooth renewal exists in mammals.

Figures

Fig. 1.
Fig. 1.
Variations in tooth replacement in reptiles and mammals, and serial addition of molars in mammals. (A) Schematics of dentitions of different vertebrates showing the left half of the lower jaws. Replacement teeth form at the lingual side of the dental arch. Mammalian molars are added serially in the posterior direction. Most reptiles have a homodont dentition, which is continuously replaced. Humans and ferrets represent typical mammals with a heterodont dentition composed of incisors, one canine, premolars and molars, and all teeth except molars are replaced once. Mice have one continuously growing incisor, a toothless diastema region and three molars. Mouse teeth are not replaced. (B) Reconstruction of human deciduous tooth germs illustrating their connection by the continuous dental lamina and the initiation of replacement tooth formation by budding of the successional dental lamina. Lingual view of anterior tooth germs in the lower jaw. A similar dental lamina is present in most other mammals and squamate reptiles. C, permanent canine; dC, deciduous canine; dI, deciduous incisor; dP, deciduous premolar; I, permanent incisor; M, molar; P, permanent premolar.
Fig. 2.
Fig. 2.
Sox2 is localized to primary dental lamina and to lingual dental epithelium during mouse molar development. (A,B) Whole-mount in situ hybridization showing expression of Sox2 mRNA (purple) in mouse lower jaw at E11 in the primary dental lamina (A), and at E12 in oral epithelium and lingual to the tooth placodes (B, dashed circles). (C-H) The expression of Sox2 mRNA (red, C-E) and protein (brown, F-H) in the lower molar from E12 to E16 is gradually restricted to lingual dental epithelium (arrows). Arrowheads in E point to Sox2 expression in E16 cervical loops. Arrow in H points to budding of dental epithelium at the lingual side of molar at E16 (inset shows higher magnification). dc, dental cord; Lab, labial; Lin, lingual; OEE, outer enamel epithelium; SR, stellate reticulum; T, tongue. Scale bars: 100 μm.
Fig. 3.
Fig. 3.
Sox2 expression localizes to dental lamina and successional dental lamina during ferret tooth replacement. (A) Schematic of frontal sections showing development of the ferret permanent canine (C), which will later replace the deciduous canine (dC). (B) Schematic sagittal and buccal view of the developing ferret tooth row showing the deciduous canine (dC), deciduous second (dP2), third (dP3) and fourth premolar (dP4), and first molar (M1) connected by the dental lamina (dl). Dashed lines in B indicate the sites of sections in C-E (dC), F-H (dP3) and I,J (dl) and in Fig. 5D (M1). (C-J) Localization of Sox2 protein (brown) during ferret tooth replacement. Arrows point to Sox2 expression in lingual dental epithelium. Asterisks indicate the Sox2-negative free end in the successional dental lamina, and in the dental lamina between deciduous teeth. Sox2 localizes also to the cervical loops and inner enamel epithelium (C-H, arrowheads). A and C-J are frontal sections, lingual to the right; B is a sagittal view, posterior to the right. Scale bars: 100 μm.
Fig. 4.
Fig. 4.
Sox2 expression localizes to dental lamina and successional dental lamina during continuous tooth replacement in five reptile species. (A-O) Localization of Sox2 protein (brown) in American alligator [embryonic stages (Es) 19-24] (A-D), green iguana (juvenile) (E-G), leopard gecko (post-hatching juvenile) (H-J), 60-day post-oviposition ball python (K-M) and 30-day post-oviposition corn snake (N,O). Arrows in alligator and iguana point to Sox2 expression in the lingual dental epithelium (A,B,C,F). Note that there is no lingual asymmetry in Sox2 expression in snakes (L,N). Sox2 expression is absent from the free end of the successional dental lamina (asterisks) in all species except gecko. Staining in the deposited enamel in gecko is non-specific (I, arrowhead). Boxed areas in K represent higher magnifications in L and M. Dashed lines outline the dental epithelium. 1°, first generation tooth; 2°, second generation tooth; dl, dental lamina; OEE, outer enamel epithelium; sl, successional dental lamina. Scale bars: 100 μm.
Fig. 5.
Fig. 5.
Sox2 expression is associated with successional formation of posterior molars in mouse and ferret. (A) Schematic of successional development of molars (see text for details). (B) Localization of Sox2 protein (brown) in E18 mouse molars. Sox2 is expressed in the dental cord and dental lamina connecting M1 to M2, and in the rudimentary dental lamina bud above M1 (arrow). Sox2 is expressed in the bud, which will form M3. Arrowheads point to Sox2 expression in M1 cervical loops. (C) Dynamics of Sox2 expression (green) during successional addition of molars. A dissected E14.5 M1 of a Sox2-GFP reporter mouse gives rise to M2 and M3 during 14 days of culture. The buds of M2 and M3 express Sox2-GFP but the completed crowns of M1 after 6 days (6d) and M2 after 9 days (9d) do not express Sox2-GFP. Arrows point to the GFP+ dental lamina, which will give rise to a new tooth. Dashed lines outline the tooth germs. (D) Localization of Sox2 protein (brown) in ferret M1 at E34 in frontal sections from anterior (a) to posterior (c). The planes of sections are shown by dashed lines in Fig. 3B. Sox2 localizes to the lingual OEE (a, arrow) and cervical loops of M1 (a, arrowheads). In the posterior end of M1 from where M2 develops, Sox2 localizes both to lingual and labial sides of M1 epithelium (b,c). Lingual is towards the right. CL, cervical loop; dc, dental cord; dl, dental lamina; IEE, inner enamel epithelium; M, molar; OEE, outer enamel epithelium; SR, stellate reticulum. Scale bars: 100 μm.
Fig. 6.
Fig. 6.
Genetic fate mapping demonstrates that successional molars derive from Sox2+ cells. (A) Timing of tamoxifen administration and analysis of Sox2Cre-ER;R26RlacZ molars. (B-D) lacZ expression (blue) in X-Gal-stained whole-mount samples of M1 cultured for 0.5, 6 and 12 days after tamoxifen administration at E13.0. Arrow in B points to the posterior end of the M1 from where the M2 develops. Dashed line outlines the dental epithelium in B and the whole tooth germs in C and D. (E-H′) Histological sections from whole-mount samples shown in B-D. The sections in E and F were cut in the frontal plane at positions indicated by black dashed lines in B, other sections were cut in the sagittal plane. Dashed lines in E and F mark the border between epithelium and mesenchyme. Boxed area of M2 shown at higher magnification in H′ shows lacZ expression in all dental epithelial cell layers. dl, dental lamina; IEE, inner enamel epithelium; M, molar; OEE, outer enamel epithelium; SR, stellate reticulum. Scale bars: 100 μm.
Fig. 7.
Fig. 7.
Conditional deletion of Sox2 leads to hyperplastic dental epithelium of M2 and M3. Hematoxylin and Eosin-stained serial frontal sections of mandibular molars of control and Sox2cKO mice at E18 and P0. Sox2cKO shows no obvious phenotype in M1 (data for P0 not shown), whereas in M2 the dental cord is expanded (arrows) and dental lamina between M2 and M3 is expanded. M3 is attached to oral epithelium by an extended sheet of dental lamina (arrowheads). See also supplementary material Fig. S2. dc, dental cord. Lingual is towards the right. Scale bars: 100 μm.
Fig. 8.
Fig. 8.
Sox2 expression is associated with epithelial competence of dental lamina in different modes of successional tooth formation. Schematic of the localization of Sox2 (red) in the primary dental lamina in the lower jaw, and in the dental lamina during different types of successional tooth formation: mammalian tooth replacement, continuous replacement and molar addition. The drawings also illustrate the morphological similarity between the two modes of successional tooth formation. 1°, first generation tooth; 2°, second generation tooth; A, anterior; B, buccal; dc, dental cord; dC, deciduous canine; dl, dental lamina; L, lingual; Le, left; M, molar; P, posterior; Ri, right; sl, successional dental lamina; t, tongue.

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