Interactions Between Twist1 and Tcf12 in Craniofacial Development

描述（由申请人提供）：颅骨和面部异常是最常见的出生缺陷之一，这些缺陷通常会阻碍受影响儿童的身心发育。在正常发育的儿童中，颅骨是由被称为缝合线的纤维关节连接起来的，当大脑生长和扩张时，缝合线可以释放压力。颅缝闭锁是新生儿和婴儿中存在的这些缝合线的过早融合。saethree - chotzen综合征是一种以颅缝闭锁和其他面部不规则为特征的疾病，十多年来，人们一直认为它是由一种名为TWIST1的基因突变引起的。在老鼠和斑马鱼身上，Twist1的功能是将某些细胞委派为外切间质，这种组织后来会形成头骨和面部骨骼。当胚胎发育时，一个Twist1拷贝的突变导致颅缝闭合，这是由缝合区域早期组织祖细胞的维护缺陷引起的。最近，我们的合作者在saethree - chotzen综合征的一小部分个体中发现了相关基因TCF12的突变，但不携带TWIST1突变。Tcf12编码一种蛋白质，该蛋白质属于一类（I类bHLH），已知该蛋白质与另一类蛋白质（II类bHLH）结合，而Twist1属于这类蛋白质。我们提出Tcf12和Twist1共同作用，指导细胞成为外切间质并维持缝合线。为了支持这一观点，tcf12和twist1基因在斑马鱼的外切间质形成期间都有表达。在小鼠中也显示，Tcf12和Twist1各一个拷贝的突变会导致一组特定缝合线的完全融合。单个Twist1拷贝的突变只会导致部分突变

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.