This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cleft palate is one of the most common craniofacial malformations in humans, impacting approximately 1 in 1000 live births. However the molecular mechanisms governing secondary palate formation prior to fusion are not well understood. We have recently discovered that mice deficient in the Prrx1 homeobox transcription factor display a cleft palate defect resulting from a lack of vertical palate elevation in 100% of homozygous offspring. This defect is more severe in Prrx1/Prrx2 double deficient embryos. Recently, a SNP study identified PRRX1 as a candidate gene in cleft palate birth defects. Therefore, our Prrx mutant mice are a relevant and novel mouse model that may facilitate uncovering the genetic circuitry involved in normal secondary palate and cleft formation. Our published and unpublished findings show that several extracellular matrix genes are direct downstream targets of Prrx1 and strongly expressed during secondary palate development. Our preliminary data demonstrates that Prrx1 binds specifically to the promoter of the proteoglycan versican, both in vitro and in vivo. Additionally our data shows that at early onset of dysmorphogenesis in the secondary palate of Prrx1 deficient mice, versican levels are dramatically increased in the palatal shelves compared to WT littermates. Since Prrx1 is strongly expressed in secondary palatal mesenchyme at E13.5 we hypothesize that Prrx1 directly regulates the expression of versican during secondary palate formation and plays a role in palatal shelf elevation during secondary palate morphogenesis.
Aims outlined in the proposal will further characterize the dysmorphogenesis of the secondary palate in the Prrx deficient embryos and the corresponding levels of versican. We will examine the changes in cellular behavior of palatal mesenchyme in the Prrx1 deficient embryos compared to WT littermates. Finally we will determine the pathways altered in the Prrx deficient palatal shelves to begin to elucidate the role of Prrx1 in the genetic circuitry of secondary palate development.
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