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Role of Hoxa2 and its Putative Downstream Target Htra1 in Osteogenic Differentiation of the Palatal Mesenchyme

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.

Description

Keywords

Cleft palate, Osteogenesis, Hoxa2, Htra1

Citation

Degree

Doctor of Philosophy (Ph.D.)

Department

Pharmacy and Nutrition

Program

Pharmacy

Part Of

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DOI

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