dc.contributor.advisor	Alcorn, Jane
dc.contributor.committeeMember	Blackburn, David
dc.contributor.committeeMember	Kulyk, William
dc.contributor.committeeMember	Eames, Brian
dc.contributor.committeeMember	Krone, Patrick
dc.creator	Iyyanar, Paul Pown Raj 1987-
dc.creator.orcid	0000-0003-0327-5395
dc.date.accessioned	2018-04-26T17:18:53Z
dc.date.available	2019-04-26T06:05:09Z
dc.date.created	2018-06
dc.date.issued	2018-04-26
dc.date.submitted	June 2018
dc.date.updated	2018-04-26T17:18:54Z
dc.description.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.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/10388/8531
dc.subject	Cleft palate, Osteogenesis, Hoxa2, Htra1
dc.title	Role of Hoxa2 and its Putative Downstream Target Htra1 in Osteogenic Differentiation of the Palatal Mesenchyme
dc.type	Thesis
dc.type.material	text
local.embargo.terms	2019-04-26
thesis.degree.department	Pharmacy and Nutrition
thesis.degree.discipline	Pharmacy
thesis.degree.grantor	University of Saskatchewan
thesis.degree.level	Doctoral
thesis.degree.name	Doctor of Philosophy (Ph.D.)

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

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