PRRX REGULATION OF EXTRACELLULAR MATRIX GENES DURING CRANIOFACIAL DEVELOPMENT

PRRX 对颅面发育过程中细胞外基质基因的调控

• 批准号: 8360490
• 负责人: Christine Bruins Kern
• 金额: $ 7.03万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360490
• 关键词: Behavior; Binding; Candidate Disease Gene; Centers of Research Excellence; Cleaved cell; Cleft Palate; Congenital Abnormality; Data; Defect; Development; Embryo; Extracellular Matrix; Funding; Genes; Genetic; Grant; Homeobox; Human; In Vitro; Live Birth; Mesenchyme; Molecular; Morphogenesis; Mus; Mutant Strains Mice; National Center for Research Resources; Oral health; Palate; Pathway interactions; Play; Principal Investigator; Proteoglycan; Publishing; Regulation; Research; Research Infrastructure; Resources; Role; Secondary Palate; Source; South Carolina; United States National Institutes of Health; cost; craniofacial; early onset; in vivo; malformation; mouse model; novel; offspring; palatal shelves; promoter; transcription factor; versican

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 Our published and unpublished findings show that several extracellular matrix genes are direct downstream targets of Prrx1 and strongly expressed during secondary palate development.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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 腭裂是人类最常见的颅面畸形之一，影响大约千分之一的活产儿。然而，控制融合前次级腭形成的分子机制尚不清楚。我们最近发现，缺乏 Prrx1 同源盒转录因子的小鼠表现出腭裂缺陷，这是由于 100% 的纯合后代缺乏垂直腭抬高所致。这种缺陷在 Prrx1/Prrx2 双缺陷胚胎中更为严重。最近，一项SNP研究将PRRX1确定为腭裂出生缺陷的候选基因。因此，我们的 Prrx 突变小鼠是一种相关且新颖的小鼠模型，可能有助于揭示与正常次级腭和裂隙形成有关的遗传回路。我们已发表和未发表的研究结果表明，一些细胞外基质基因是 Prrx1 的直接下游靶标，并在次级上颚发育过程中强烈表达。我们的初步数据表明，Prrx1 在体外和体内均与蛋白多糖多功能蛋白聚糖的启动子特异性结合。此外，我们的数据显示，在 Prrx1 缺陷小鼠的次级腭形态发生早期发生时，与 WT 同窝小鼠相比，腭架中的 versican 水平显着增加。由于 Prrx1 在 E13.5 的次级腭间充质中强烈表达，我们假设 Prrx1 在次级腭形成过程中直接调节多功能蛋白聚糖的表达，并在次级腭形态发生过程中在腭架抬高中发挥作用。该提案中概述的目标将进一步表征 Prrx 缺陷胚胎中次级腭的畸形发生以及相应的多功能蛋白聚糖水平。我们将检查与 WT 同窝出生的 Prrx1 缺陷胚胎相比，腭间充质细胞行为的变化。最后，我们将确定 Prrx 缺陷腭架中改变的途径，以开始阐明 Prrx1 在次级腭发育遗传电路中的作用。