Species-specific sensitivity to TGFβ signaling and changes to the Mmp13 promoter underlie avian jaw development and evolution

Developmental control of jaw length is critical for survival. The jaw skeleton arises from neural crest mesenchyme and previously we demonstrated that these progenitors upregulate bone-resorbing enzymes including Matrix metalloproteinase 13 ( Mmp13) when generating short quail beaks versus long duck bills. Inhibiting bone resorption or Mmp13 increases jaw length. Here, we uncover mechanisms establishing species-specific levels of Mmp13 and bone resorption. Quail show greater activation of, and sensitivity to Transforming Growth Factor-Beta ( TGFβ ) signaling than duck; where mediators like SMADs and targets like Runx2, which bind Mmp13 , become elevated. Inhibiting TGFβ signaling decreases bone resorption. We discover a SMAD binding element in the quail Mmp13 promoter not found in duck and single nucleotide polymorphisms (SNPs) near a RUNX2 binding element that affect expression. Switching the SNPs and SMAD site abolishes TGFβ-sensitivity in the quail Mmp13 promoter but makes duck responsive. Thus, differential regulation of TGFβ signaling and Mmp13 promoter structure underlie avian jaw development and evolution. ### Competing Interest Statement The authors have declared no competing interest.