AUTHOR=Iyyanar Paul P. R. , Nazarali Adil J. 

TITLE=Hoxa2 Inhibits Bone Morphogenetic Protein Signaling during Osteogenic Differentiation of the Palatal Mesenchyme

JOURNAL=Frontiers in Physiology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2017.00929

DOI=10.3389/fphys.2017.00929

ISSN=1664-042X

ABSTRACT=<p>Cleft palate is one of the most common congenital birth defects worldwide. The homeobox (<italic>Hox</italic>) family of genes are key regulators of embryogenesis, with <italic>Hoxa2</italic> having a direct role in secondary palate development. <italic>Hoxa2</italic><sup>−/−</sup> mice exhibit cleft palate; however, the cellular and molecular mechanisms leading to cleft palate in <italic>Hoxa2</italic><sup>−/−</sup> mice is largely unknown. Addressing this issue, we found that <italic>Hoxa2</italic> regulates spatial and temporal programs of osteogenic differentiation in the developing palate by inhibiting bone morphogenetic protein (BMP) signaling dependent osteoblast markers. Expression of osteoblast markers, including <italic>Runx2, Sp7</italic>, and <italic>AlpI</italic> were increased in <italic>Hoxa2</italic><sup>−/−</sup> palatal shelves at embryonic day (E) 13.5 and E15.5. <italic>Hoxa2</italic><sup>−/−</sup> mouse embryonic palatal mesenchyme (MEPM) cells exhibited increased bone matrix deposition and mineralization <italic>in vitro</italic>. Moreover, loss of <italic>Hoxa2</italic> resulted in increased osteoprogenitor cell proliferation and osteogenic commitment during early stages of palate development at E13.5. Consistent with upregulation of osteoblast markers, <italic>Hoxa2</italic><sup>−/−</sup> palatal shelves displayed higher expression of canonical BMP signaling <italic>in vivo</italic>. Blocking BMP signaling in <italic>Hoxa2</italic><sup>−/−</sup> primary MEPM cells using dorsomorphin restored cell proliferation and osteogenic differentiation to wild-type levels. Collectively, these data demonstrate for the first time that <italic>Hoxa2</italic> may regulate palate development by inhibiting osteogenic differentiation of palatal mesenchyme via modulating BMP signaling.</p>