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

Abstract

Precise developmental control of jaw length is critical for survival, but underlying molecular mechanisms remain poorly understood. The jaw skeleton arises from neural crest mesenchyme (NCM), and we previously demonstrated that these progenitor cells express more bone-resorbing enzymes including Matrix metalloproteinase 13 (Mmp13) when they generate shorter jaws in quail embryos versus longer jaws in duck. Moreover, if we inhibit bone resorption or Mmp13, we can increase jaw length. In the current study, 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 and overexpressing Mmp13 in NCM shortens the duck lower jaw. To elucidate the basis for this differential regulation we examine the Mmp13 promoter. We discover a SMAD binding element and single nucleotide polymorphisms (SNPs) near a RUNX2 binding element that distinguish quail from duck. Altering the SMAD site and switching the SNPs abolishes TGFβ-sensitivity in the quail Mmp13 promoter but makes the duck promoter responsive. Thus, differential regulation of TGFβ signaling and Mmp13 promoter structure underlie avian jaw development and evolution.

Squamous papilloma involving the mandible: A case report and descriptive literature review

“…Such alterations may encompass changes in bone matrix hardness and the cytokine profile, such as interleukin (IL) and tumor necrosis factor (TNF)-α. During the inflamed state, the dysregulated activity of TGF-β signaling may reverse the inhibition of cell proliferation ( 26 , 27 ). This reversal in turn can lift the inhibitory restrictions tumor cells, contributing to their aberrant growth.…”

“…Furthermore, TGF-β may enhance the migratory and invasive capabilities of tumor cells ( 28 , 29 ), enabling them to infiltrate neighboring tissues, blood vessels or lymphatic vessels. Simultaneously, TGF-β may also dampen the immune system's ability to identify and eliminate tumors ( 27 , 29 ). It was also noteworthy that chronic stress and the sympathetic nervous system may have involvements in the tumor in the present cases, where the persistent inflammation may have activated the sympathetic nervous system.…”

Genomic organization, intragenic tandem duplication, and expression analysis of chicken TGFBR2 gene

“…It has been shown that there are marked species differences in TGF-β signaling pathway ( Kruithof et al, 2012 ). For example, chickens had significantly higher TGF-β signaling activity in lower jaw skeleton than ducks ( Smith et al, 2022 ). Chickens and mice exhibited distinct TGF-β ligand expression patterns during the epithelial to mesenchymal cell transformation ( Azhar et al, 2003 ; Molin et al, 2003 ) and had contradictory requirements for the TGF-β ligands and receptors during the endocardial-to-mesenchymal cell transformation ( Jiao et al, 2006 ; Yamagishi et al, 2012 ).…”

Extreme lower jaw elongation in a placoderm reflects high disparity and modularity in early vertebrate evolution

“…understanding the early evolution and evolvability of neural crest derived structures, including teeth and jaws [41,42]. Past research on jaw length regulation suggests that the anatomy of Alienacanthus most likely resulted from derived modifications in one or multiple pathways involving the transforming growth factor-beta, the bone morphogenetic proteins, the sonic hedgehog pathway members or the fibroblast growth factor [43][44][45]. In halfbeak fishes specifically, the calmodulin molecule paralogue calm1, known to play a generic role in bone cell proliferation, was identified as a potential regulator of jaw length, with its differential expression in upper and lower jaws [46].…”