Experimental approach to developmental anomalies in human dentition

It has been assumed that there exist two parallel horseshoe-shaped epithelial structures during early development in human jaws: the internally located dental lamina, giving rise to single tooth primordia, and the externally located vestibular lamina, giving rise to the oral vestibule. The oral vestibule (vestibulum oris) is the part of the oral cavity that separates the gums and teeth from the lips and cheeks. It arose as an ancient essential structure in mammals, enabling the sucking and so feeding of siblings with maternal milk.

Although a thickening of the vestibular epithelium is always present on serial histological sections, computeraided three-dimensional reconstructions did not show any continuous vestibular lamina. On the contrary, several discontinuous epithelial structures (bulges and ridges) were documented, transiently occurring at different stages of oral vestibule development in both the upper and lower jaws. Along the mesiodistal axis, the dental and vestibular epithelia were regionalized in parallel: in the incisive, canine and first and second molar regions. The vestibular ridges fused with the dental lamina distally to the deciduous canine, first molar and second molar in the upper jaw. The segmentation and heterogenous developmental base of the oral vestibule have been described also in the lower jaw. These interactions between the developing teeth and vestibular structures seem to be reminiscent of the situation in some reptiles, where single teeth are paired one-to-one with single tooth glands. The complex development of the epithelium of oral vestibule and its developmental relationship to dentition might explain origin of some pathologies that postnatally occur in the oral vestibule of human (Hovoraková et al, 2005, 2007).

However, molecular mechanisms of odontogenic process can only be studied using experimental animal models (mouse, rat, shrew, ferret, pig...) and consequently extrapolated to human. Mouse odontogenesis is the most frequently used model not only in tooth developmental studies, but also in the studies on general rules of molecular regulation of organogenesis. Mouse adult dentition is strongly reduced comprising only one incisor and three molars in each jaw quadrant. A toothless diastema occurs at the place of missing teeth. However, former descriptive studies in mouse embryos have shown that not only prospective functional teeth, but also transient rudimentary tooth primordia develop there that have been related to teeth in mouse ancestors. The rudiments either regress at assistance of apoptosis, or take a part during functional teeth development. Thus the mouse embryonic dentition provides an ideal system for studies of organ progression and regression, and of their molecular control (Peterková et al, 2006).

The mouse odontogenesis model posses a very important advantage at molecular level. Spontaneously mutant or genetically manipulated mice allow performing studies and experiments focused to understanding the role of specific molecular factors during normal and pathological development. A frequent phenotype of dental anomalies in mutant mice is the existence of a supernumerary tooth. In the Sprouty mutant mice, the supernumerary tooth develops from revitalization of the rudimentary tooth primordia; the revitalization includes decrease of physiological apoptosis and increase of proliferation (Peterková et al, 2009; Charles et al, 2011).

The knowledge on normal mouse odontogenesis is a precondition for understanding developmental role of specific genes in the mouse model. There are some new data on tooth development in normal mice that open new questions and new areas for future research.

1) The existence of three consequently appearing Shh (Sonic hedgehog) expression domains, which differed in time and position has been documented in the cheek region in mice.

Shh is expressed in dental epithelium during odontogenesis being considered as a marker of early tooth development. It has been shown, using Shh expression that two rudimentary tooth buds (MS and R2 rudiments) initiate the sequential development of the mouse molars and these have previously been mistaken for early stages of M1 development. Although neither rudiment progresses to form an adult tooth, the posterior one merges with the adjacent M1, which may explain the anterior enlargement of the M1 during mouse family evolution (Prochazka et al, 2010).

2) Multiple Shh expression has been documented during the early incisor development in mice.

Instead of one large incisor expression domain, which is generally correlated with functional incisor development, we found two sequentially appearing Shh expression areas in the incisor region of the mouse mandible (Hovorakova et al, 2011):

• the earlier, anterior and more superficial Shh area related to the rudimentary incisor;
• the later, posterior and deeper Shh expression of the prospective functional incisor.

3) A contribution of epithelial cells from the early Shh expression domain to vestibulum oris formation has been shown.

We used the Shh reporter mice, where the cells previously expressing Shh are labelled in blue. The labelled cells have been found in the incisors primordia as well as in the anterior part of the epithelial anlage of oral vestibule. The presence of the labelled cells in the vestibular epithelium documented that these cells or their predecessors had expressed Shh in the former common Shh expression domain in the incisor region at earliest stages of the tooth development (Hovorakova et al, 2011).

These results shed new light on the normal tooth development in mice and will help in understanding some pathologies found in mouse mutants. The possibility of the usage of many mutant mouse strains also opens the mouse odontogenesis model to the intensive research in the area of human pathologies and diseases. At molecular level, there are human genetic syndromes (e.g. hypohidrotic ectodermal dysplasia or Apert syndrome) that have their homology or are based on the same genetic background like genetic disorders in available mutant mice (e.g. Tabby/EDA or Sprouty mutant mice, respectively).

Acknowledgement: CZ: GA ČR: GA304/09/1579, CZ: GA ČR: P305/12/1766.

References:

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