Role of homeobox genes
Recent studies of the role of homeobox genes indicate that the expression of these genes in ectomesenchymal tissues may control the development and ultimate shape of the tooth.11,18–20 Homeobox genes constitute a large family of genes that specify correct positioning of body parts during embryonic development. These genes are implicated in determining axial patterns, such as the anteroposterior development of limbs. All members of this family share a common code for a 60–amino acid DNA-binding sequence (the homeodomain) that allows the protein to act as a gene regulatory factor. Homeobox genes (Dlx, Pax, Msx, etc) are widely expressed in embryonic craniofacial tissues. Whiting21 has reviewed their role in normal development as well as the developmental defects that result from mutations.
Studies of tooth development in mice that have mutant homeobox genes support the idea that regional expression of various homeobox genes may provide the positional information for the type of tooth to be formed.11 The results of these studies indicate that mutations in Dlx1 and Dlx2 genes prevent maxillary molar development but have no negative effect on maxillary incisor development. Incisor development is regulated by Msx1 and Msx2 homeobox genes. Thus, according to Thomas et al,11 the odontogenic pattern (ie, tooth type and position in the arch) is determined by early regional and restricted expression of various combinations of homeobox genes. Once the tooth buds are formed, the homeobox genes are activated in a more generalized pattern. The presence of Msx1 is required for progression of molar tooth development beyond the bud stage.20,22
Karg et al23 described the localization of the homeobox gene, S8 (Prx2), in the dental papillae of developing mouse incisor and molar tooth buds. Because the highest level of S8 expression occurs during the growth of the dental papilla, it was suggested that S8 might take part in regulating the overall growth of the developing tooth. At the cap stage of tooth development, epithelial growth centers (enamel knots) regulate the cuspal outline of the developing tooth by coordinating cell proliferation within the enamel organ and dental papilla through the secretion of growth factors.24,25
Progress in research on gene expression in tooth development can be found on the Internet at http://bite-it.helskini.fi.26
Histogenesis of the tooth
The enamel organ develops by proliferation of cells in the dental lamina. The adjacent ectomesenchymal cells continue to proliferate and concentrate to form the dental papilla and dental sac (see Fig 1-2). During this coordinated growth, various growth factors and regulatory proteins are exchanged between the epithelium and ectomesenchyme.
During the early stage of tooth development, the enamel organ, shaped like a cap, is superimposed over a condensation of ectomesenchymal cells (Figs 1-2, 1-6, and 1-7a). At the cap stage, the enamel organ is subdivided into four regions: the outer enamel epithelium (OEE), the stellate reticulum (SR), the stratum intermedium (SI), and the inner enamel epithelium (IEE) (see Fig 1-6).27–30 Later in development, the enamel organ is bell shaped, encompassing a well-defined dental papilla along its concave internal surface (Fig 1-7b).
The cells of the OEE are cuboidal and separated from the adjacent dental sac ectomesenchyme by a basement membrane. Along their concave surface, they contact the star-shaped cells of the SR. The cells of the SR are separated by wide intercellular spaces. Adjacent SR cells remain in contact via long cytoplasmic folds joined by numerous desmosomes and gap junctions (see Fig 1-6). The intercellular spaces of the SR contain hyaluronan and chondroitin sulfates that bind large amounts of water.31 The SR retains its hydrated state until the initiation of enamel formation; thereafter, the SR and the OEE differentiate into the papillary layer (described in chapter 3).
The SI consists of one or two layers of low cuboidal cells situated between the SR and the IEE (see Fig 1-6). A clearly defined SI is established between the SR and the IEE just prior to the differentiation of the ameloblasts. The cells of the SI and IEE express similar enzyme patterns, suggesting that both cell types have common metabolic functions.
The cells of the IEE are juxtaposed to the ectomesenchymal cells (preodontoblasts) of the dental papilla (Figs 1-6 and 1-8). The basement membrane beneath the IEE consists of a basal lamina densa and many aperiodic fibrils (see Fig 1-8). The nature of these fibrils and their significance in odontoblast differentiation are discussed in chapter 2.
Fig 1-6 Enamel organ and dental papilla. The outer enamel epithelium (OEE) forms the convex surface of the enamel organ and is separated from adjacent dental sac (DS) cells and general mesenchyme (not shown) by a basement membrane. The stellate reticulum (SR) lies between the OEE and the stratum intermedium (SI). The SI cells are closely juxtaposed to the cells of the inner enamel epithelium (IEE). The enamel knot (EK) represents a small group of nondividing cells near the IEE. The IEE is separated from the preodontoblasts (PO) of the dental papilla by a basement membrane (see Fig 1-8). (DL) Remnant of the dental lamina.
Cytodifferentiation of odontoblasts and ameloblasts starts at the tip of the future cusps. Under the influence of stimuli originating from the IEE, the preodontoblasts begin differentiation. In turn, they stimulate the cells of the IEE to undergo differentiation to form a single layer of enamel matrix–secreting cells, the ameloblasts. Preodontoblasts reach maturity as secretory odontoblasts before the preameloblasts mature into secretory ameloblasts. Regulatory control of cell proliferation and the differentiation of ameloblasts and odontoblasts is provided in part by complex sequential interactions involving cell membrane receptors, growth factors, and/or matrix molecules concentrated in the IEE basal lamina. Recent research has begun to define regulatory signals in tooth development at the level of gene activation.32,33
Figs 1-7a and 1-7b Three-dimensional reconstructions of enamel organs made from serial sections of human embryos. Dental papilla and mesenchyme not shown. (Adapted from Ooe74 with permission.)
Fig 1-7a Cap stage.
Fig 1-7b Bell stage.
Fig 1-8 Role of basement membrane components at the junction between the preameloblast (PA) of the inner enamel epithelium (IEE) and the adjacent preodontoblast (PO). A basement membrane consisting of a lamina