ROLE OF MSX GENE EXPRESSION IN CRANIOFACIAL DEVELOPMENT

人类的发展过程是由程序控制的 胚胎内的基因表达。出生缺陷是导致 儿科人群的发病率和死亡率，因此代表 这是一个重大的公共卫生问题。畸形综合征由以下原因引起 破坏发育调节的胃部或环境因素 基因表达程序。转录因子是细胞周期调节因子。 定义胚胎发生的遗传程序。同源盒基因编码 含有60个氨基酸结构域的转录因子，能够 这些基因在发育过程中起着至关重要的作用。 MSX-1和MSX-2是发育中表达的同源结构域蛋白 哺乳动物的心脏、四肢和颅面结构 胚胎发生，尤其是在重要的上皮间充质部位 感应性组织相互作用。波士顿型颅骨融合症是一种 常染色体显性遗传的畸形综合征 四肢和头面部发育。人类MSX2基因的一个突变 在患有这种疾病的患者中得到了证实，这种疾病导致了 组氨酸取代进化上保守的原氨酸残基 在同源结构域的第7位。 拟议研究的长期目标是确定 MSX-1和MSX-2同源结构域蛋白在正常颅面中的作用 编码基因突变的发生和机制 这些蛋白质可能导致人类颅面畸形综合征。 本项目的具体目标是：(1)建立发病机制 经分子生物学和胚胎学鉴定为波士顿型颅脑融合症 突变型和野生型MSX-2蛋白的体外表达分析 组织培养细胞与小鼠体内发育；L和(Ii) 确定小鼠体内正常的MSX-1基因表达是否受到干扰 发育也会导致头面部畸形综合征。这些 研究将进一步加深我们对MSX蛋白在 为颅面发育研究提供模型系统 颅面畸形，并建立了关键的联系 MSX蛋白作为转录调控因子的功能 以及它们在指导人类颅面发育中的作用 胚胎发生。

The process of human development is controlled by programs of regulated gene expression within the embryo. Birth defects are a major cause of morbidity and mortality in the pediatric population and thus represent a significant public health problem. Malformation syndromes result from gastric or environmental factors that disrupt developmentally-regulated programs of gene expression. Transcription factors are mediators of the genetic programs that define embryogenesis. Homeobox genes encode transcription factors containing a 60 amino acid domain that is capable of binding to DNA and these genes play essential roles in development. Msx-1 nd Msx-2 are homeodomain proteins that are expressed in developing cardiac, limb, and craniofacial structures during mammalian embryogenesis, especially at sites of important epithelio-mesenchymal inductive tissue interactions. Craniosynostosis, Boston type is a malformation syndrome with autosomal dominant inheritance that affects limb and craniofacial development. A mutation in the human MSX2 gene has been demonstrated in patients with this disorder that results in a substitution of histidine for an evolutionarily-conserved prokine residue at position 7 of the homeodomain. The long-term goal of the proposed research is to determine the role that MSX-1 and MSX-2 homeodomain proteins play in normal craniofacial development and the mechanisms by which mutations in the genes encoding these proteins may result in human craniofacial malformation syndromes. The specific aims of this project are (i) to establish the pathogenesis of craniosynostosis, Boston type by molecular biologic and embryologic analyses of mutant and wild-type Msx-2 protein expression in vitro within tissue culture cells and in vivo murine development;l and (ii) to determine whether disruption of normal Msx-1 expression during murine development also results in a craniofacial malformation syndrome. These studies will further our understanding of the role of Msx proteins in craniofacial development, provide model systems for the study of craniofacial malformations, and establish a crucial link between the function of Msx proteins as putative transcriptional regulatory factors and their role in directing craniofacial development during human embryogenesis.