Coordination of trigeminal axon navigation and patterning with tooth organ formation: epithelial-mesenchymal interactions, and epithelial Wnt4 and Tgfβ1 regulate semaphorin 3a expression in the dental mesenchyme

Abstract

During development, trigeminal nerve fibers navigate and establish their axonal projections to the developing tooth in a highly spatiotemporally controlled manner. By analyzing Sema3a and its receptor Npn1 knockout mouse embryos, we found that Sema3a regulates dental trigeminal axon navigation and patterning, as well as the timing of the first mandibular molar innervation,and that the effects of Sema3a appear to be mediated by Npn1 present in the axons. By performing tissue recombinant experiments and analyzing the effects of signaling molecules, we found that early oral and dental epithelia, which instruct tooth formation, and epithelial Wnt4 induce Sema3aexpression in the presumptive dental mesenchyme before the arrival of the first dental nerve fibers. Later, at the bud stage, epithelial Wnt4 and Tgfβ1 regulate Sema3a expression in the dental mesenchyme. In addition, Wnt4 stimulates mesenchymal expression of Msx1transcription factor, which is essential for tooth formation, and Tgfβ1 proliferation of the dental mesenchymal cells. Thus, epithelial-mesenchymal interactions control Sema3a expression and may coordinate axon navigation and patterning with tooth formation. Moreover, our results suggest that the odontogenic epithelium possesses the instructive information to control the formation of tooth nerve supply.

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

“…5 Histologically, the pioneer dental axons have been shown to emerge from the deep mandibular inferior alveolar nerve, where they grow toward the first molar tooth germ at embryonic (E) day 12.5. [21][22][23][24] Approximately half a day later, the first dental axons reach the target area of the bud-stage tooth germ. During the tooth-specific morphogenetic cap and bell stages, nerves innervate the tooth germ, to surround Figure 1.…”

“…32,23,13,25,26 the mesenchymal dental follicle target area, which ultimately forms the periodontium (during root formation and tooth eruption) that attaches roots to alveolar bone. 10,13,23,25,26 Of note, although the nerves already surround the developing tooth organ during embryonic stages, axons will only grow into the mesenchymal dental pulp post-natally. Typically this occurs after a delay of about 10 days (from the first encounter of axons with the tooth target), on postnatal day 3-4.…”

“…38,39,40,41,42,43 mRNAs for SEMA3A, which repels both sensory and sympathetic nerves, 41 displays developmentally regulated and distinct cellular expression patterns in both epithelial and mesenchymal tissue during mouse molar and incisor development. 23,26,44,45 Sema3A is specifically expressed in sites that are devoid of navigating axons, suggesting functions in tooth innervation. During the onset of tooth formation and innervation, Sema3A is expressed in the dental and jaw mesenchyme areas, adjacent to the pioneer nerve branch (the trigeminal 'molar nerve') growing toward the early tooth germ.…”

Roles of innervation in developing and regenerating orofacial tissues

“…These molecules generally attract the growth cones. Nerve ingrowth towards the dental epithelium and the dental papilla is actively inhibited and regulated by semaphorins, and by semaphorin3a in particular [58]. Semaphorin3a is expressed in the dental follicle and directs the growth of trigeminal axons along precise paths [58].…”

Tissue Engineering for Tissue and Organ Regeneration

“…The innervation of the tooth is initiated relatively late during development and involves sensory and sympathetic nerves. Complex molecular mechanisms regulate the timing and pattern of tooth innervation (Fried et al, 2007;Kettunen et al, 2005;Luukko et al, 2008). It has been suggested that the epithelium instructs and controls dental axons navigation in the dental mesenchyme (Luukko et al, 2008).…”