PITX HOMEOBOX GENE FAMILY IN CRANIOFACIAL DEVELOPMENT

人类发育是一个复杂的过程，涉及胚胎发育不同阶段的多个基因相互作用，并与重要的环境覆盖。在过去的几年里，转录因子在早期发育中的作用以及这些基因的中断对正常结构的影响已经变得越来越明显。我们最近发现人类RIEG1(PITX)基因是一种新的双类同源框基因，与Rieger综合征有关，Rieger综合征以前房缺陷、牙齿发育不良和脐带异常为主要表现。这个家族的第二个成员(PITX3)刚刚在我们的实验室被发现，其中一个突变导致眼前段间充质发育不良(ASMD)。在这个计划中，我们将通过鉴定由这些基因的异常引起的其他人类头面部疾病以及通过对基因发育级联的详细研究来扩大我们对这些转录因子的研究。该项目的具体目标将包括：1)Rieger类基因的更多特征，包括它们的DNA结构，识别新的类成员和与公认的调控序列同源的基因。还将开展进一步的家庭和个人特征研究，尤其是那些表型包括头面部异常的家庭和个人；2)将进行基于表达的研究，包括涉及小鼠模型的组织特异性研究；3)使用转基因动物作为研究上位相互作用的模型系统，包括建立两个Rieger类基因的敲除小鼠，以及利用Rieger相关基因和具有相似或互补表达模式的基因进行互补研究。这个项目的结果将是扩大我们对面部结构缺陷原因的理解，以及对一类新的同源框基因的发育生物学的详细理解，这些基因被证明是发育中的关键。将开发可用于研究基因-基因和基因-环境相互作用的模型，以进一步了解基础生物学、治疗学和预防。扩大的表型与特定突变的相关性以及研究这些基因-基因和基因-环境相互作用的能力为全面了解一类新的同源盒基因在人类出生缺陷和成人疾病中的作用提供了机会。该项目将直接与项目3(RUSSO)互动，该项目将研究PITX基因的蛋白质-蛋白质相互作用，并与项目4和5以及临床和分子核心进行接口。

Human development is a complex process involving multiple gene interactions at various stages of embryogenesis and with important environmental overlays. In the last few years, the role of transcription factors in early development and the impact that disruptions in these genes can have on normal structures has become increasingly evident. We have recently identified the human RIEG1 (PITX) gene as a novel bicoid- class homeobox gene responsible for Rieger syndrome, which has anterior chamber defects, dental hypoplasia and umbilical abnormalities as primary manifestations. A second member of this family (PITX3) has just been identified in our laboratory in which a mutation causes the disorder anterior segment mesenchymal dysgenesis (ASMD). In this proposal, we will expand our studies of these transcription factors, through identification of additional human craniofacial disturbances caused by abnormalities in these genes and by detailed studies of the genes developmental cascade. Specific goals of the project will include: 1) additional characterization of the Rieger class genes, including their DNA structure, the identification of new class members and of gene homologous to the recognized regulatory sequences. Further characterization of families and individuals, with a particular focus on those whose phenotype includes craniofacial anomalies will also be carried out; 2) expression-based studies will be performed that will included tissue-specific studies involving the mouse model; 3) the use of transgenic animals as a model systems for the study of epistatic interactions, including the development of knockout mice for two of the Rieger-class genes and the initiation of complementation studies using Rieger-related genes and genes with similar or complementary expression patters. The outcome of this project will be an expansion of our understanding of the causes of facial structural defects, as well as a detailed understanding of the developmentally biology of a new class of homeobox genes shown to be critical in development. Models will be developed that can be used for studies of gene-gene and gene-environment interactions to further our insights into basic biology, therapeutics and prevention. The correlation of expanded phenotypes with specific mutations and the ability to study these for gene-gene and gene- environment interaction affords a opportunity for a comprehensive understanding of a new class of homeobox genes for their role in human birth defects and adult disease. This project will directly interact with Project 3 (Russo) which will study protein-protein interactions of the PITX genes and interface with projects 4 and 5 and the clinical and molecular cores, as well.