Role of Hoxa2 and its Putative Downstream Target Htra1 in Osteogenic Differentiation of the Palatal Mesenchyme
Year: 2018
Type: dissertation
Abstract: Cleft palate is one of the most common structural birth defects in humans. Hoxa2 is the most anteriorly expressed gene of the homeobox family that define the anterior-posterior axis during embryonic development. Hoxa2 is expressed in the palatal shelves and plays an intrinsic role regulating cell proliferation. Hoxa2-/- mice develop cleft palate, albeit the cellular and molecular mechanisms remain to be explored. In this thesis, I have tested the hypothesis that Hoxa2 inhibits osteogenic differentiation of the palatal mesenchyme. I present here evidence that loss of Hoxa2 results in increased canonical BMP signaling dependent osteogenic program spatially and temporally in the developing Hoxa2-/- palatal shelves in vivo and in Hoxa2-/- MEPM cells in vitro. In the second part of this thesis, I investigated the role of a serine protease Htra1, a putative downstream target of Hoxa2 in osteogenic differentiation of the palatal mesenchyme. The results indicate that Htra1 is a positive regulator of osteogenic differentiation and is upregulated in the Hoxa2-/- palatal shelves. In addition, I identified that Runx2, a master regulator of osteogenic differentiation, binds to the proximal promoter region of Htra1 to induce its expression. Collectively, the data reveals that aberrant osteogenic signaling in the Hoxa2-/- palatal shelves due to increased osteoprogenitor commitment and proliferation may lead to cleft palate in these mice. In addition, I show for the first time that Htra1 is a novel direct downstream target of Runx2 during osteogenic differentiation. In summary, this thesis contributes to a better understanding of the cellular and molecular mechanisms governing osteogenic differentiation in the palatal mesenchyme during normal palate development and in cleft palate pathogenesis.
Author: Paul P. R. Iyyanar
Language: English
Subfield: Oral Surgery
Field: Dentistry
Domain: Health Sciences
Open Access status: green
Awards: G3233715258, G3254083750
OpenAlex ID: W2803030232