Interactions Between Twist1 and Tcf12 in Craniofacial Development

Twist1 和 Tcf12 在颅面发育中的相互作用

• 批准号: 8784033
• 负责人: Camilla Sue Teng
• 金额: $ 3.71万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784033
• 关键词: Affect; BHLH Protein; Binding; Biological Assay; Brain; Branchial arch structure; Calvaria; Cell Line; Cells; Child; Chotzen Syndrome; Co-Immunoprecipitations; Complex; Congenital Abnormality; Craniosynostosis; Data; Defect; Development; Disease; Embryo; Face; Functional disorder; Genes; Genetic; Growth; Helix-Turn-Helix Motifs; Human; Imagery; In Vitro; Individual; Joint structure of suture of skull; Joints; Knockout Mice; Laboratories; Ligation; Maintenance; Mesenchyme; Mesoderm; Modeling; Mus; Mutation; Neural Crest; Neural Crest Cell; Newborn Infant; Phenotype; Population; Proteins; Role; Skeleton; Stem cells; Surgical sutures; TWIST1 gene; Testing; Time; Tissues; To specify; Zebrafish; base; bone; cell type; coronal suture; coronal synostosis; craniofacial; cranium; face bone structure; innovation; insight; loss of function; mental development; mouse model; mutant; premature; pressure; progenitor; public health relevance; suture fusion; transcription factor

DESCRIPTION (provided by applicant): Skull and facial abnormalities are among the most common birth defects, and such defects often hinder the physical and mental development of the affected child. In a normal developing child, skull bones are connected by fibrous joints called sutures, which allow pressure to be released as the brain grows and expands. Craniosynostosis is the premature fusion of these sutures that are present in newborns and infants. Saethre-Chotzen syndrome, a disorder characterized by craniosynostosis and other facial irregularities, has been known for over a decade to be caused by mutations in a gene called TWIST1. In mice and zebrafish, Twist1 functions to delegate certain cells to become ectomesenchyme, which is tissue that will later form the skull and facial bones. When the embryo is developing, mutations in one copy of Twist1 result in craniosynostosis, which is caused by defective maintenance of early tissue progenitors in the suture regions. Recently, our collaborator has identified mutations in a related gene, TCF12, in a subset of individuals who present with Saethre-Chotzen syndrome but do not carry TWIST1 mutations. Tcf12 encodes a protein that belongs to a class (class I bHLH) that is known to bind to another class of proteins (class II bHLH), which Twist1 belongs. We propose that Tcf12 and Twist1 function together as one to instruct cells in becoming ectomesenchyme and maintain sutures. In support of this, both tcf12 and twist1 genes in zebrafish are expressed during the time the ectomesenchyme is forming. Also shown in mice, mutations in one copy of each Tcf12 and Twist1 result in complete fusion of a particular set of sutures. Mutations in one copy of Twist1 alone result in only partial premature suture fusion in mice. Here, I use strengths of both zebrafish and mouse models to investigate potential functions of Tcf12-Twist1 molecules in both ectomesenchyme specification and suture maintenance. My findings will better reveal the genetic basis of premature fusion of skull bones in Saethre-Chotzen syndrome.

描述（由申请人提供）：颅骨和面部畸形是最常见的出生缺陷之一，这些缺陷往往会阻碍受影响儿童的身心发育。在正常发育的儿童中，颅骨由称为缝合线的纤维关节连接，随着大脑的生长和扩张，这些关节可以释放压力。颅缝早闭是新生儿和婴儿中存在的这些缝的过早融合。Saethre-Chotzen综合征是一种以颅缝早闭和其他面部不规则为特征的疾病，十多年来一直被认为是由一种名为TWIST 1的基因突变引起的。在小鼠和斑马鱼中，Twist 1的功能是代表某些细胞成为外胚间充质，这是后来形成头骨和面骨的组织。当胚胎发育时，Twist 1的一个拷贝中的突变导致颅缝早闭，这是由缝合区早期组织祖细胞的缺陷维持引起的。最近，我们的合作者已经确定了一个相关基因TCF 12的突变，在一个患有Saethre-Chotzen综合征但不携带TWIST 1突变的个体亚组中。Tcf 12编码属于一类（I类bHLH）的蛋白质，已知该蛋白质与Twist 1所属的另一类蛋白质（II类bHLH）结合。我们认为Tcf 12和Twist 1共同起作用，指导细胞成为外胚间充质并维持缝合。为了支持这一点，斑马鱼的tcf 12和twist 1基因在外胚间充质形成期间表达。同样在小鼠中显示，Tcf 12和Twist 1的一个拷贝中的突变导致一组特定缝线的完全融合。Twist 1的一个拷贝中的突变仅导致部分突变。 小鼠的过早缝合融合。在这里，我使用斑马鱼和小鼠模型的优势，调查Tcf 12-Twist 1分子在外胚间充质规格和缝合维护的潜在功能。我的发现将更好地揭示Saethre-Chotzen综合征中颅骨过早融合的遗传基础。