Integration of tooth morphogenesis and innervation by local tissue interactions, signaling networks, and semaphorin 3A.

The tooth, like many other organs, develops from both epithelial and mesenchymal tissues, and has proven to be a valuable tool with which to investigate organ formation and peripheral innervation. Tooth formation is regulated by local epithelial-mesenchymal tissue interactions, and is closely integrated with stereotypic dental nerve navigation and patterning. Recent analyses of the function and regulation of semaphorin 3A (SEMA3A) have shed light on the regulatory mechanisms that coordinate organogenesis and innervation at the tissue and molecular levels. In the tooth, SEM3A acts as a developmentally regulated secretory chemo-repellent, that controls tooth innervation during embryonic and postnatal development. The tooth germ governs its own innervation by a combination of local tissue interactions and SEMA3A expression. SEMA3A signaling, in turn, is controlled by a number of conserved signaling effectors, including TGF-β superfamily members, FGF, and WNT; all function in embryo and organ development, and are essential for tooth histo-morphogenesis. Thus, SEMA3A driven axon guidance is integrated into key odontogenic signaling networks, establishing this protein as a critical molecular tether between 2 distinct developmental processes (morphogenesis and sensory innervation), both of which are required to obtain a functional tooth.