Control of Meckel’s Cartilage Degradation during Mandibular Development

Meckel’s cartilage (MC) is a transient scaffold for lower jaw development whose degradation is essential for normal mandibular morphogenesis, with defects leading to micrognathia or mandibular dysmorphogenesis. Here we investigate the timing and tissue interactions controlling MC degradation using transgenic mouse models, explant culture, and grafting experiments. Our results show that the initiation signal for degradation occurred in a window around embryonic day (E) 14.5, with induction of Runx2 and subsequent formation of hypertrophic cartilage. Loss of teeth in mouse mutants, removal of tooth germs ex vivo, or grafting tooth germs to ectopic sites did not affect degradation initiation, showing that developing teeth are neither necessary nor sufficient to initiate MC breakdown. In contrast, conditional neural crest deletion of Runx2 and, independently, loss of Msx1 prevented initiation of the degradation cascade despite retention of the dentary bone body in Msx1 mutants, identifying a signal from the dentary mesenchyme, rather than the tooth or the bone itself, as the extrinsic trigger. RUNX2 additionally played a second, cell-intrinsic role, driving the endochondral program once expressed within MC itself. Grafting experiments at E14.5–15 showed that proximal MC, outside the normal distal degradation zone, was not competent to respond to ectopic bone or tooth grafts at this stage. Separately, inhibition of vasculogenesis did not prevent chondrocyte hypertrophy but blocked subsequent cartilage clearance, implicating VEGF-dependent vasculature in a distinct, later step of chondroclast recruitment. Together, these findings define a 2-stage degradation cascade—extrinsic dentary mesenchyme-derived initiation followed by intrinsic RUNX2- and VEGF-dependent execution—and establish that neither teeth nor the physical presence of bone are sufficient to trigger MC breakdown.