Principles of tooth development

Individuals of all animal species develop from a single cell, a fertilized oocyte. The development
includes a massive amount of cell divisions (proliferation), cell differentiation, migration
and also cell death. The cells of an early embryo of higher animals are capable to
adapt all cell fates, and they may be regarded as embryonic stem cells. During further development, the cells become parts of tissue layers and their options for regulative developmentbecome more and more limited. Their fates are regulated by their interactions, limiting theiroptions and causing a stepwise commitment to more restricted cell fates (Gilbert, 2003).However, the cells may still retain a capacity to regulation: cells that will contribute to a certainorgan may be able to develop into a normal organ even though part of them is removed.For example, if an early mouse tooth germ is split into two, both halves develop into teeth ofnormal size and morphology (Glasstone, 1963). The terminal differentiation is associatedwith a reduced capacity to proliferate. In many adult tissues, however, some cells have retainedstem cell-like properties and a capacity to provide new differentiated cells (Fuchs etal., 2004).

In many animals, the unfertilized oocyte is polarized allowing the sperm entry only on certain
regions (Gilbert, 2003). The site of the sperm entry further delineates the future development,
e.g. the planes of the first cell divisions, and creates the basis for polarity in the
growing embryo. Further guides for the prospective commitment of the cells is served by
their position in the growing embryo and by their interactions with other cell and tissues.
Commitment, morphogenesis and differentiation are regulated by inductive interactions between cells and groups of cells. The positional information may be conveyed from organizingtissues through gradients of inductive substances, often called morphogens, as well as oftheir antagonists (Hogan, 1999; Gilbert, 2003). Inherent for development and morphogenesisof many organs are self-organizing processes that are thought to act for example during formationof somites from the paraxial mesoderm as well as during positioning of ectodermalplacodes and cusps of teeth (Weiss et al., 1998; Salazar-Ciudad and Jernvall, 2002; Giudicelliand Lewis, 2004; Sick et al., 2006)

In instructive interactions, the inducer dictates the commitment of a responder while in permissive interactions the properties of the inducer are needed to allow the commitment of theresponder (Gilbert, 2003). For an induction to happen, the responder must have previouslyacquired a competence to respond. In the key inductive interaction called primary embryonicinduction the dorsal blastopore lip, the Spemann organizer, inducts the neural tube and thedorsal axis. Subsequent inductive evens leading to the development of individual organshave been called secondary inductions (Saxen and Thesleff, 1992; Gilbert, 2003). For manyorgans, inductive interactions between epithelium and mesenchyme are important, and developmentof teeth and hair are examples of reciprocal process of epithelial-mesenchymalinteractions (Mina and Kollar, 1987; Thesleff and Nieminen, 2005).

Each cell has the same genome, but they express different sets of genes in different levels.The morphology, behaviour and interactions with other cells as well as the commitment andcompetence are based on the gene products the cell synthesizes. Aberrations of the regulationof gene expression may lead to abnormal growth and cancer. The capacity to gene expressionis largely executed through expression of transcription factors that are the proteinsregulating the expression of genes. Interactions between cells may be mediated by the adhesionmolecules in the cell surface and by the extracellular matrix that cells secrete (Gilbert,2003; Thesleff et al., 1991).

However, instructive interactions typically involve productionof signaling molecules ("signals"), often peptides or proteins, which are then bound to a specificreceptor on the surface of (or in some cases, inside) the “receiving” cells (Gilbert,2003; Pires-daSilva and Sommer, 2003; Wang and Thesleff, 2005). The signals may act in paracrine fashion between neighbouring or close-residing cells but they may also exert theireffects on relatively long range and on a concentration dependent manner (Gilbert, 2003; Fanet al., 1995; Gritli-Linde et al., 2001). Most important signals are peptide growth factors thatbelong to the evolutionarily conserved Wnt, Heghehog and fibroblast growth factor (Fgf)families as well as to the transforming growth factor-􀁅 (TGF􀁅) superfamily including e.g.TGF􀁅s, bone morphogenetic proteins (BMPs), and activins (Logan and Nusse, 2004; PiresdaSilvaand Sommer, 2003; Kitisin et al., 2007).

Other important signals include the tumornecrosis factors (TNFs), epidermal growth factor (EGF) family, neurotrophins and Notchligands. In addition to these signals mediated by peptide ligands, retinoid acid has been consideredas a morphogenic signal (Gilbert, 2003). Cells that are competent to receive the signals must express receptors for each signaling protein(ligand) family (Fig. 1). Binding of a ligand to its receptor or receptor complex leads tomediation of the signal into the cell which through protein interactions activates certain transcriptionfactors thus regulating gene expression (Gilbert, 2003) (Pires-daSilva and Sommer,2003). The response of a cell to a signal depends on its competence and may be cell division,apoptosis, change of commitment (cell fate), differentiation or production of a reciprocal signal,often of a different signal family, or an extracellular or intracellular antagonist of signaling.Different signals may act synergistically or antagonistically and they may be attenuatedby signaling antagonists .

The signaling, the signaltransduction, activation of specific transcription factors, and subsequent responses are conservedduring the development of different organ systems and through evolution and can beregarded to constitute modules of genetic networks which are used in variable manners andin different combinations during different stages of organogenesis in different species.