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

腭裂是人类最常见的先天性出生缺陷之一，其发生率为1:700至1:1000。继发性腭裂可以作为一种孤立的先天缺陷（非综合征）与唇裂一起发生，也可以作为另一种综合征的一部分。遗传和环境因素在腭裂的发展中都起作用。最近的研究还表明，在腭裂患者身上观察到的广泛的其他影响，例如寿命明显缩短，所有主要死因的风险增加。腭裂的影响是多样而复杂的，对调节腭裂发生的因素尚未完全了解。次级上颚的发育是由一个复杂的通路网络调控的，这些通路共同作用，密切调节上颚的关键细胞过程，包括细胞生长、细胞死亡和细胞迁移。在小鼠中，双侧腭架在胚胎第11.5天（E11.5）作为上颌突的外植物首次发育。然后，舌架垂直向下生长，直到E14.0，之后，舌架经历一个快速的提升，成为水平方向。然后，升高的腭架彼此生长，直到每个腭架接触并融合形成第二腭。我们对参与次腭发育过程的所有信号分子还没有明确的认识。我们实验室有突变小鼠群体（Hoxa2 -/-小鼠），表现出继发性腭裂的高发。使用这些小鼠作为模型系统，我们的目标是确定在调节腭发育中起作用的机制。特别是，我们将研究Hoxa2基因如何在腭发育中受到调节，以及Hoxa2结合的其他基因（下游目标：Htra3和Six2基因）在腭发育中与Hoxa2协同发挥什么作用。本研究将促进我们对腭裂形成的理解，并为腭裂组织生长和形成的多种信号通路之间的相互作用提供重要信息。

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.