Numerous clinical issues require surgical reconstruction of the mandible, but this type of treatment has a number of contraindications. An important obstacle in developing alternative, regenerative treatment options is that humans cannot efficiently regenerate bone. Thus, Daniel Youngstrom and colleagues look to uncover the molecular basis of mandible regeneration following surgical mandibulectomy in zebrafish, which are capable of large-scale skeletal regeneration. Using a novel reporter consisting of mCherry under the control of the Notch-responsive her6 promoter, they demonstrate that Notch signalling is activated during early healing. Pharmacological inhibition of Notch signalling reduces the volume, surface area and mineral content of bone, whereas Notch overexpression has the opposite effect. Moreover, they find that inhibition of Notch signalling causes reduced proliferative expansion and osteogenic conversion of the regenerative callus during the early regenerative process. In contrast, Notch overexpression promotes osteogenic differentiation of callus mesenchymal cells and an overall increase in cell proliferation. Proteomic analysis of fish overexpressing Notch shows an upregulation of enzymes for aerobic glycolysis, suggesting that Notch signalling promotes increased energy availability to speed up bone regeneration. Given the conserved role of Notch signalling in mammalian bone regeneration, these findings may lay the groundwork to help develop alternative strategies to support mandibular regeneration in humans.
