Expression and functional analysis of novel downstream targets of Hoxa2 and epigenetic regulation of Hoxa2 in the developing mouse

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Cleft palate is one of the most common congenital birth defects in humans, occurring with a frequency of 1:700 to 1:1000 live births. A cleft secondary palate can occur as an isolated birth defect (non-syndromic) in conjunction with a cleft lip or as a part of another syndrome. Both genetic and environmental factors play roles in the development of cleft palate. Recent studies also demonstrate a wide range of additional effects observed in individuals with a cleft palate, such as a significantly shorter lifespan with an increased risk for all major causes of death. The effects of cleft palate are diverse and complex, and a complete understanding of the factors in regulating palatogenesis has yet to be achieved. The development of the secondary palate is regulated by a complex network of pathways that work together to tightly regulate critical cellular processes in the palate, including cell growth, cell death, and cell migration. In the mouse, bilateral palate shelves first develop as outgrowths from the maxillary processes at embryonic day 11.5 (E11.5). The shelves then grow vertically down either side of the tongue until E14.0 after which the shelves undergo a rapid elevation to become horizontally oriented towards one another above the tongue. The elevated palatal shelves then grow towards one another until each shelf contacts and fuses to form a secondary palate. We do not have a clear understanding of all the signaling molecules involved in the process of secondary palate development. Our lab has the mutant mouse colony (Hoxa2 -/- mice) that exhibit high incidence of secondary cleft palate. Using these mice as a model system, our goal is to identify what mechanisms come to play in regulating palate development. In particular, we will investigate how Hoxa2 gene is regulated in palate development and what role the other genes that Hoxa2 binds to (downstream targets: Htra3 and Six2 genes) play in concert with Hoxa2 in palate development. This research will advance our understanding of cleft palate formation and provide important information regarding the crosstalk among diverse signalling pathways that govern tissue growth and formation of developing palate.