Salivary glands develop from a simple epithelial bud to a complex organ during embryonic development by the process of branching morphogenesis. Extracellular matrix molecules and signal transduction pathways regulate the dynamics of this complicated process. Fibronectin, laminin γ2, and tissue inhibitor of metalloproteinases-3 are differentially expressed in developing clefts or buds of submandibular glands. Integrin receptors for fibronectin and laminin cooperate with site-specific, developmentally regulated gene expression of fibronectin in this process. Fibronectin-mediated crosstalk between integrin cell-to-matrix and cadherin cell-to-cell adhesion systems promotes the formation of clefts. A particularly important intracellular signaling regulator of branching morphogenesis is phosphatidylinositol (PI) 3-kinase, which generates signaling lipids such as PIP3. This enzyme and several different growth factors regulate branching. Experimental manipulation of either the fibronectin/integrin or the PI 3-kinase/PIP3 systems can control branching morphogenesis.
Conclusion: Progress in understanding the mechanisms of salivary branching morphogenesis promises to provide novel approaches to future tissue engineering or regeneration of damaged salivary glands.
Keywords: salivary gland, branching morphogenesis, extracellular matrix, signal transduction, PI 3-kinase, T7-SAGE