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Death in the Life of a Tooth

¹ Academy of Sciences, Institute of Animal Physiology and Genetics, Veveri 97, 602 00 Brno, Czech Republic;
² Department of Craniofacial Development and Orthodontics and
³ Department of Craniofacial Development, Floor 28, GKT Dental Institute, King’s College, Guy’s Hospital, London Bridge, London SE1 9RT, UK;

^* corresponding author, paul.sharpe{at}kcl.ac.uk

	ABSTRACT

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
Programmed cell death (apoptosis) constitutes an important mechanism in embryonic development. Although there is substantial evidence for essential roles of apoptosis in organ shaping and controlling of cell number, the mechanisms of these processes are poorly understood. The regulation of cell proliferation to form tooth buds of the appropriate size and at the correct positions must involve a balance between cell division and cell death. Apoptosis has been suggested to play both passive and active roles in bud formation and morphogenesis and in reduction of the dental lamina, as well as silencing of the enamel knot signaling centers. The location of apoptotic cells during tooth development has been described and suggests their temporospatial roles. Unfortunately, there is little functional evidence on these roles, and the aim of this review is to highlight areas where apoptosis may play key roles in odontogenesis.

KEY WORDS: apoptosis • tooth development

	WHAT IS KNOWN

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
Apoptosis (programmed cell death) is a genetically regulated and finely tuned process of cell elimination essential for the embryogenesis, development, and tissue homeostasis of multicellular organisms. Cell death occurring during embryogenesis has been recognized for decades, but only recently have two types of cell death—necrosis and apoptosis—been distinguished and described (Kerr et al., 1972). Although there is clear evidence that apoptosis controls tissue shape during morphogenesis (for review, see Meier et al., 2000), the mechanisms and signaling pathways involved in these processes are poorly understood. In some organs, such as the kidney, apoptosis is speculated to be associated with cell differentiation to balance the numbers of epithelial and mesenchymal cells.

Teeth are examples of epithelial-mesenchymal organs and are often used as a model for studying the nature of epithelio-mesenchymal interactions and signaling controlling morhogenesis, histogenesis, and cytodifferentiation (Fig. 1). Mouse molars have also been used for in vitro experiments to test the specific roles of different molecules in odontogenesis (for review, see Thesleff and Sharpe, 1997; Cobourne and Sharpe, 2003).

View larger version (26K): [in this window] [in a new window]   Figure 1. Enamel organ at the bell stage.

	APOPTOSIS IN TOOTH MORPHOGENESIS

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

At the initiation stage of mouse tooth development, no apoptotic cells are observed in the epithelial thickening or in the surrounding mesenchyme before E12.5. At E12.5, morphologically corresponding to the early bud stage, apoptotic cells are found in the budding epithelium, in particular in the cells facing the oral cavity. During further development, at the late bud stage, when the tooth germ prolongs its central axis, apoptotic cells become concentrated at the tip of the tooth bud. At the bud stage, no apoptotic cells are observed in the mesenchyme surrounding the budding epithelium. When the tooth germ reaches the cap stage, this cluster of apoptotic cells is still apparent and becomes localized within the epithelial enamel knot. During further development (E14.5–15), the number of apoptotic cells increases but, interestingly, without any evident loss of the cell mass, suggesting a rapid replacement by high-proliferating cells surrounding the enamel knot. With disappearance of the primary enamel knot, apoptosis is no longer observed in this area but is detected in the gubernaculum (epithelium joining the enamel organ to the buccal epithelium). At the cap stage, a few apoptotic cells are detectable in the condensed dental mesenchyme, but these show no restricted pattern.

Tooth crown morphogenesis and cytodifferentiation occur during the bell stage. At this time (E16-newborn), apoptosis is evident in secondary enamel knots and in stratum intermedium cells adjacent to the enamel knots. Some scattered apoptotic cells are also found in the mesenchyme. In the newborn mice, apoptosis continues in the dental lamina and in the adjacent enamel epithelium. In post-natal mice, no apoptosis is detected in the dental mesenchyme (Fig. 2).

View larger version (27K): [in this window] [in a new window]   Figure 2. Mouse molar tooth development from initiation to bell stages. Apoptotic cell distribution (black spots) and gene expression in the epithelial and mesenchymal cells of molecules mentioned in the review. No apoptosis is observed in the thickening of oral epithelim (white) prior to E12.5, when apoptosis is shown in the surface of the dental epithelium (A) and is extended to the tip of the growing tooth bud (B). At the cap stage (C), apoptosis is detected in the dental lamina and in the primary enamel knot. At the bell stage, apoptotic cells are found in the dental lamina, dental follicle, outer enamel epithelium, and secondary enamel knots (D). Few scattered apoptotic cells are also detectable in the dental mesenchyme (grey, italic).

All teeth, regardless of shape or identity, pass through the same developmental stages and consist of the same tissues (Stock et al., 1997). Apoptotic cells were also found during incisor development (Kieffer et al., 1999). At the early incisor cap stage, only low apoptotic activity is observed within the oral epithelium, and apoptotic cells are concentrated at the future tip of the tooth. At E13.5, apoptotic cells and bodies are localized in two distinct areas in the epithelial compartment: in the stalk (connecting the anterior part of the enamel organ with the oral epithelium) and in the prospective inner dental epithelium close to the epithelio-mesenchymal junction. At E14.0, accumulation of apoptosis is also found in the oral epithelium above and behind the posterior end of the enamel organ. Interestingly, there is no relation between apoptosis and the posterior growth of the incisor.

	APOPTOSIS IN DIASTEMAL TOOTH PRIMORDIA

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
In rodent dentition, transient epithelial primordia originate in the diastema (non-tooth-forming region) between the incisor and molar tooth germs, and phylogenetic and molecular arguments support the dental nature for these rudiments. The diastemal rudiments reach the bud stage before their regression, which is associated with cell death.

Apoptotic elimination of these vestigial tooth buds in diastema has been documented (Turecková et al., 1996; Peterková et al., 2000) and gene expression described (Keränen et al., 1999) (Fig. 3). Apoptosis occurs with prevalence in the buccal part of the epithelium of the diastemal dental primordia and extends later to the whole epithelium of the dental rudiments. Apoptosis is also observed in the dental lamina interconnecting the rudiments with the incisor and molar epithelium, and a few apoptotic cells are scattered in the adjacent mesenchyme.

View larger version (8K): [in this window] [in a new window]   Figure 3. Mouse diastemal dental primordium and its regression by apoptosis (black spots).

	APOPTOSIS IN ENAMEL KNOTS

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

Apoptotic cells are found in enamel knots of both molar and incisor teeth. In molars, the appearance of apoptosis is strictly linked to elimination of cells within the primary enamel knots and is also detectable in areas of secondary enamel knots. In incisors, however, apoptosis at the tip of the forming tooth appears prior to any evidence of histological arrangement of the enamel knot.

The fact that little or no apoptosis is found in the incisor enamel knots suggests that disappearance of the enamel knot in the incisor might result from re-organization of its cells at the histological level (Kieffer et al., 1999). It may be speculated that apoptosis occurring in the cells surrounding the incisor enamel knot has a role in shaping the one-cusp crown of these teeth. A single enamel knot is formed in incisors, which are shaped with one cusp, while more enamel knots form in molars, which have multiple cusps, indirectly supporting a role for apoptosis in tooth crown formation.

	APOPTOSIS IN AMELOBLASTS AND ODONTOBLASTS

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
During enamel formation, about 50% of the ameloblasts between late secretory and late maturation stages undergo cell death—25% immediately at the start of maturation and the remaining 25% throughout the subsequent regions of the maturation zone (Smith, 1998). Apoptosis seems to provide a means to regulate ameloblast cell number by elimination of daughter cells during pre-ameloblast mitosis.

Apoptosis can be detected at different stages of enamel development: in differentiating pre-ameloblasts, in a few late secretory ameloblasts, in transitional ameloblast and adjacent stratum intermedium cells, and in maturing ameloblasts (Bronckers et al., 2000).

At advancing stages of dentinogenesis, odontoblasts become crowded by the reduction in pulp space. The decrease in number can be explained either by formation of a pseudostratified layer or by the apoptotic elimination of an important percentage of odontoblasts.

Apoptosis in odontoblasts has been shown in rodent incisors and also in human molars of different ages (Franquin et al., 1998). Secondary dentin deposition, associated with odontoblast re-organization as a single layer, results in a hyperbolic decrease in odontoblast number, which seems to result from massive programmed cell death.

	APOPTOSIS IN PERIODONTAL TISSUES

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
Apoptosis seems to have a role during tooth eruption, as shown in erupting mouse incisors studied by light and electron microscopy (Schellens et al., 1982). The mechanism of cell death in the periodontal ligament of teeth during eruption may be different from that in the periodontium of erupted teeth of limited growth, such as molars of adult rodents (Bronckers et al., 2000). Periodontal ligament cells of the incisor are removed by apoptosis just below the junctional epithelium.

When the enamel organ of the tooth germ is fully developed, amelogenesis begins at the tip of prospective cusps, and at this site the overlying stellate reticulum begins its involution (Baratella et al., 1999). The involution involves decrease in intracellular spaces, invasion of blood vessels, appearance of macrophage-like cells, and, significantly, a reduction in the number of stellate reticulum cells via apoptosis.

	APOPTOSIS-RELATED MOLECULES AND SIGNALING IN TOOTH DEVELOPMENT

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
Mammalian teeth develop from a series of increasingly well-characterized reciprocal interactions between oral ectoderm cells and neural-crest-derived mesenchyme. These interactions are largely (but not exclusively) mediated by exchange of cell-signaling proteins and downstream activation of gene transcription. The instructive signals for odontogenesis come from the oral ectoderm and include members of the FGF, BMP, Wnt, and Shh families (Thesleff and Sharpe, 1997). These proteins bind to receptors on mesenchyme cells, which respond by participating in odontogenesis and by sending signals back to the dental ectoderm. Planar signaling within the ectoderm and mesenchyme is also evident.

The molecular machinery responsible for apoptosis exhibits a high degree of conservation in the course of evolution. During embryonic programmed cell death, members of different groups of apoptosis regulators have been identified (for review, see Meier et al., 2000).

Cell death signals are communicated through two main types of biochemical pathways in mammalian cells. The intrinsic apoptotic machinery is switched on mainly as a response to DNA damage, whereas the extrinsic pathways may play a role in developmental apoptosis evoked by extracellular signaling. The intrinsic apoptotic signals originate largely from the mitochondria, whereas the extrinsic pathways are triggered by the activation of death receptors belonging to the TNF-receptor superfamily (e.g., CD95, TNFR1, DR1, DR2). These death receptors are found on the plasma membrane of many cells, and, when triggered by binding of the corresponding cell ligands, the death receptors initiate the rapid activation of a class of caspases, inducing apoptosis execution. Death receptors are proposed to signal through various adaptors, such as FADD, TRADD, or RAIDD.

Caspases are key effector components of apoptosis. The 15 currently identified mammalian caspases constitute a family of intracellular cysteine proteases that initially are produced as inactive zymogens (procaspases). Caspases may be divided into two functional subfamilies: initiator caspases, which are involved in upstream regulatory events; and effector caspases, which are directly responsible for cell disassembly events.

To date, there is little evidence concerning the molecules involved in death-receptor-mediated signaling during tooth development. Fas (CD 95) receptor and Fas ligand have been shown to play a role in jaw bone development; however, their involvement in tooth development remains unclear and may be down-regulated by Bcl-2 molecules (Hatakeyama et al., 2000). Recently, activated caspase 3 was detected in developing mouse molars (Shigemura et al., 2001). The distribution pattern of the caspase-3-positive cells in the odontogenic epithelial tissue of the developing tooth closely corresponds with the localization of TUNEL-positive cells and is restricted in the same areas as apoptotic cells: the most superficial layer of dental epithelium at the initiation stage, in the dental lamina throughout tooth germ growth, in the primary enamel knot from the late bud to the late cap stages, in areas of secondary enamel knots, and around the tips of the prospective cusps after the bell stage.

Dental apoptosis has been associated with the expression of several different molecules, in particular, transcription factors. Egr-1, N-myc, c-fos, Msx-2, and Bcl-2 are all localized in developing teeth; however, except for Msx-2 there has been no correlation with cell death in odontogenesis (Jernvall and Thesleff, 2000).

p53 tumor suppressor mRNA is strongly expressed in all tissues of the early murine embryo, including tooth germs. The general expression pattern suggests that p53 may play a role in cell cycle and transcription regulation rather than in apoptosis in developing teeth. Mice that lack p53 are developmentally normal (Donehower et al., 1992); however, p53 homologues may compensate for its function. Mice lacking p63 are born alive but have striking developmental defects, including absent teeth (Mills et al., 1999).

Apoptosis in enamel knots starts at the bud stage, correlated with the first expression of the p21 molecules (Jernvall et al., 1998). Mice deficient in p21 have no tooth defects, indicating that it does not play an essential role in tooth development (Deng et al., 1995), or molecules such as p27 or perhaps p57 may compensate for its function as seen with p53, p63, and p73, respectively (Mills et al., 1999). Nevertheless, no change in number of apoptotic cells is found in downless (Jackson) mutants, where the death domain is disrupted and expression of p21 is reduced (Tucker et al., 2000). No change in number of apoptotic cells may explain why loss of Dl (downless) results not in an enlargement or loss of enamel knots but rather in a change in shape. In downless (encoding Edar, a member of the TNF receptor family) and Tabby (encoding Eda, type II membrane protein of the TNF ligand family) mutants, the teeth are severely affected, with very shallow depressions forming instead of normal deep cusps in the molar region. However, since apoptosis in teeth seems to be independent of Eda/Edar signaling (Tucker et al., 2000), these changes in final crown morphology could be caused by defects in proliferation of the tissue surrounding enamel knots rather than by effects on programmed cell death.

	FUNCTIONAL STUDIES

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
So far, the role of apoptosis in tooth development has been suggested from the position of apoptotic cells. Evidence for these roles, however, is not as clear. A few investigators have attempted to block apoptosis in the tooth and diastemal primordia to see what affect this has on tooth morphology and number.

Diastemal tooth primordia cannot form teeth even when apoptosis is blocked (Keränen et al., 1999). This may be due to the fact that these diastemal tooth primordia show different gene expression patterns compared with those of teeth and therefore may not have the capacity to develop into real teeth. Apoptosis in this case, therefore, appears to have a passive role in removing unwanted primordial structures.

Specific activity of caspase 3 has been shown in enamel knots (Shigemura et al., 2001), although no histological changes (excluding more crowded cells in the enamel knot) were shown in molar explant cultures after pharmaceutical inhibition of caspases for 2 days at E13.5 in the mouse molars and incisors and post-culturing for 1–8 days in control medium (Coin et al., 2000). However, expression of Shh, Msx-2, Bmp-2, and Bmp-4 was down-regulated in the persistent enamel knots in these experiments. Analysis of these data would suggest that it is not essential to terminate the signaling role of enamel knots by means of apoptosis, and that the enamel knot cells terminate their instructive position (if any) by limited timing of signaling molecule expression rather than by triggering apoptosis. Thus, the role of apoptosis here would be just a mechanism to scavenge the terminated cells.

In common with other organs, growth factors (EGF, FGF-4) were shown to prevent dental apoptotis (Vaahtokari et al., 1996). When epithelial and mesenchymal components of E13-E13.5 tooth germs were separated and cultured in isolation for 16–24 hrs, apoptosis was abundant in the explants. When mesenchyme was cultured in contact with epithelium, apoptosis was prevented in both epithelium and mesenchyme at the tissue interface, whereas apoptotic cells were abundant elsewhere in the explants (Vaahtokari et al., 1996).

The localized control of dental epithelial cell proliferation appears to be mediated by Shh, which also acts as an epithelial cell survival factor at the bud stage. Breakdown in Shh signaling using pharmaceutical inhibitors in the medium induces abundant apoptosis in the tooth bud and damage of epithelial continuity at the tips of the tooth germs (Cobourne et al., 2001). Such tooth buds are able to recover this cell loss and continue their development. In this case, elimination of cells by means of apoptosis seems to support proliferation in the surrounding tissue in a similar manner to that seen in wound-healing processes (e.g., Zhu et al., 2003).

	WHAT IS NOT KNOWN YET

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
Enamel knots are suggested to play key roles as signaling centers in both incisor and molar teeth, and may also be involved in the evolution of the characteristic tooth morphologies in different mammalian species (Vaahtokari et al., 1996). Involvement of apoptosis in the life and death of enamel knots is evident; however, the exact role and mechanisms of apoptosis in enamel knot cells remain unclear.

There is also no definitive evidence concerning the origin of the secondary enamel knots. High expression of FGF-4, which is a potent mitogen, in secondary enamel knots supports the idea that these originate from a small cluster of cells derived possibly from migrating cells surviving the apoptotic massacre of primary enamel knots. However, if programmed cell death in primary enamel knots is simply a passive process to remove terminated cells, and if the silencing is based on restricted signaling of surrounding cells rather than on death signals, it is unclear how this cluster of cells, rather than others, would be distinguished for survival.

In common with other models of apoptosis, the final step of dental programmed cell death consists of the activation of caspases (for review, see Zheng et al., 1999; Hengartner, 2000). The central executioner—caspase 3—has been shown to be activated during dental apoptosis; however, there are no data concerning the activation of other caspases as employment of receptor-mediated (caspase 8) or intrinsic apoptotic pathways (caspase 9).

It has been proposed that cells are programmed to commit suicide and continuously require signals, such as peptide growth factors, from other cells to survive (Raff et al., 1993). This means that cell survival is governed by repression of the death program, which can be switched on either by lack of survival factors or by death signaling. There are no data available on whether apoptosis in tooth development occurs by activation of intrinsic pathways or by triggering death receptors. In the latter case, it must be clarified which cells are instructive for death signals and how this signaling mechanism works during the epithelial and mesenchymal cell-cell interactions occurring at different stages of embryonic tooth development.

An important question concerning apoptotic processes in embryonic systems is the origin of the phagocytes responsible for the clearance of the cell debris. This function has been assigned to the neighboring healthy cells; however, there is evidence that circulating macrophages are involved in this process and that the neighboring cells act as compensatory phagocytes (Wood et al., 2000). This would mean that with development of the immune system of the embryo, the apoptotic cells are more promptly removed and their detection can become complicated. Moreover, the apoptotic process can be very rapid: The observation that within 30 min, apoptotic cells are labeled and subsequently phagocytosed demonstrates how fast apoptosis and clearance of apoptotic cell death may take place (Savill et al., 1993; Bronckers et al., 2000). Morphological studies thus could greatly underestimate the number of apoptotic cells.

Most importantly, it remains to be clarified if dental apoptosis is an essential morphogenetic mechanism in tooth development or if this process just serves to remove unwanted cells. A passive role of apoptosis has been shown in elimination of regressive tooth diastemal primordia, where apoptosis can be considered more as a degenerative process than a process of creation. The active role of apoptosis in modeling the final shape, size, and position of the teeth has not yet been proven.

Abrogation of programmed cell death in vivo adversely affects the organism and generally has devastating consequences on development (Ranger, 2001). For this reason, the use of knock-out animals to study apoptotic pathways is limited. However, interference with apoptotic molecules and apoptotic pathways is essential to elucidate the role and mechanisms of apoptosis in tooth development.

	WHAT DOES IT ALL MEAN?

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
In developing teeth, apoptosis plays an important role during all stages, as shown in early morphogenesis, amelogenesis, dentinogenesis, and during eruption in the periodontium.

Spatially and temporally restricted distribution patterns of apoptotic cells suggest multiple roles for apoptosis in dental development:

• The reduction of the dental lamina, which is known to disappear during odontogenesis, appears to occur via apoptosis. The proper disruption of dental lamina has a high clinical significance, since its overgrowth may form cysts over the developing teeth and delay eruption (Ten Cate, 1994).
  
• Central cells of the invaginating dental epithelium undergo apoptosis, suggesting involvement in budding morphogenesis. Apoptosis in the most superficial layer of the dental epithelium (early and middle bud stages) may support proliferation of underlying basal mucosal cells.
  
• Apoptosis in the dental lamina cells prevents the mesial and vertical overgrowth of the tooth germ, and reduction of cell number in the enamel organ executed by apoptosis may have an important role in governing the final size and exact position of the tooth in the jaw. Reduction of cell number in the enamel organ executed by apoptosis may have an important role in the size of tooth germs and final teeth.
  
• Apoptosis occurring in the toothless region of dental lamina may be involved in reduction of epithelial overgrowth between teeth, which could lead to tooth appositions.
  
• Apoptosis in the diastema region leads to elimination of rudimental tooth primordia.
  
• Apoptotic processes as shown in the diastemal dental primordia may be involved in the regulation of final tooth number.
  
• A passive functional role of apoptosis in enamel knots is understood to be a general mechanism whereby the function of enamel knots is terminated.
  
• A general active role of apoptosis in morphogenesis is expected in incisor and molar shaping. Apoptotic cells are in strong correlation with removal of specific cells during silencing of enamel knots and areas of forming future cusps of the tooth. Apoptosis still seems to be an important morphogenetic mechanism in shaping the final crown tooth morphogenesis.
  

Apoptosis undoubtedly has roles in dental diseases and dismorphology, but whether any of these results from primary defects in apoptotic pathways or is a secondary consequence remains to be resolved. Certainly apoptosis may have an important role in diseases such as periodontal disease (e.g., Gamonal et al., 2001). Similarly, cell death during odontogenesis may be involved in genetic disorders such as hypodontia and agenesis. The development of extra teeth in cleidocranial dysplasia, for example, could consequently involve defects in apoptosis and a failure to remove ectopic tooth germs. Although it is unlikely that defects in apoptosis are the primary cause of dental disorders, an understanding of its secondary role could be important for treatment.

	ACKNOWLEDGMENTS

 
Work in the Brno lab is supported by the Grant Agency of the Czech Republic (204/02/P112), the work in the London lab by the Wellcome Trust and MRC. Cooperation was supported by EMBO.

Received May 12, 2003; Last revision September 8, 2003; Accepted September 10, 2003

	REFERENCES

TOP ABSTRACT WHAT IS KNOWN APOPTOSIS IN TOOTH MORPHOGENESIS APOPTOSIS IN DIASTEMAL TOOTH... APOPTOSIS IN ENAMEL KNOTS APOPTOSIS IN AMELOBLASTS AND... APOPTOSIS IN PERIODONTAL TISSUES APOPTOSIS-RELATED MOLECULES AND... FUNCTIONAL STUDIES WHAT IS NOT KNOWN... WHAT DOES IT ALL... REFERENCES

 
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