The long-term goal of this research project is to understand the molecular genetic mechanisms of craniofacial development and of cleft palate pathogenesis. Cleft palate is among the most common birth defects in humans and incurs significant social and economic burdens. Why cleft palate occurs so commonly is because the mammalian palate develops initially as two separate outgrowths from the oral sides of the maxillary processes. These outgrowths initially grow downward to form two vertical palatal shelves flanking the developing tongue and subsequently elevate to above the dorsum of the developing tongue and fuse to each other at the midline at a precise developmental stage to form the intact palate. Any disturbance of the palatal shelf growth, elevation, or fusion could result in cleft palate. Whereas recent studies have identified the Tgf-beta signaling pathway as the major molecular pathway regulating palatal shelf fusion, the molecular mechanisms underlying initial phases of palatal outgrowth and patterning have not been characterized. We recently found that the Odd-skipped family zinc-finger transcription factor, Osr2, plays critical roles in palate shelf growth and patterning. We showed that expression of the Osr2 mRNA is specifically activated in the nascent palatal mesenchyme cells before palatal outgrowth and that a targeted null mutation in the Osr2 gene causes specific defects in palatal mesenchyme proliferation, leading to delayed palatal shelf elevation and cleft palate. We demonstrated that the Osr2 mutant mice also have defects in mediolateral patterning of the palatal shelves, which correlated with a spatiotemporally regulated pattern of Osr1 mRNA expression during palatal outgrowth. These data identify the Osr1 and Osr2 genes as key intrinsic regulators of palatal growth and patterning. In addition, we found that the mouse Tbx22 gene, which is orthologous to the human TBX22 gene associated with X-linked cleft palate, exhibits a similar expression pattern with that of Osr2 during palate development. This research program investigates further the roles of Osr1, Osr2, and Tbx22 in palatal growth and patterning in mutant mouse models. Moreover, we are developing new tools to systematically dissect the molecular pathways regulating palatal growth and patterning using the tissue-specific gene inactivation strategy. These studies will provide novel insights into the molecular genetic mechanisms governing normal palate development and will ultimately lead to the development of strategies for prevention of the cleft palate birth defect.
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