ANIMAL MODELS FOR SAETHRE CHOTZEN SYNDROME

该项目的长期目标是建立和表征人类颅面部疾病综合征的小鼠模型，并了解这些疾病综合征背后的遗传和生化途径。颅骨融合，即颅骨的过早融合，是一个重大的医学问题，每3000名活产儿中就有一名发生。颅缝融合所致的颅骨发育异常可导致颅内压升高、脑血流障碍、呼吸道阻塞、视力和听力学习障碍及不良心理影响。在这项提案中，我们将研究Saethre-Chotzen综合征的小鼠模型，这是人类颅缝融合最常见的常染色体显性遗传病之一。人类TWIST基因编码一种bHLH型转录因子，其单倍性不足已被证明是Saethre-Chotzen综合征的主要原因之一。其他Saethre-Chotzen综合征家族病例是由一些编码成纤维细胞生长因子受体(FGR2和FGR3)的基因突变引起的。小鼠Twist基因的零突变导致纯合子早期胚胎死亡，而杂合子导致部分穿透性骨骼缺陷，复制了Saethre-Chotzen综合征的某些特征。人类的twist基因是果蝇twist基因的同源物。果蝇的遗传学证据表明，Twist基因的突变与由Snail基因编码的另一种转录因子的突变相互作用。我们已经在Snail的两个小鼠同源物(称为Sna和Slug)中构建了靶向突变。我们将检验这一假设，即与果蝇一样，蜗牛和扭曲家族的基因在小鼠身上都在相同的遗传途径中发挥作用。这一建议的具体目的是：1.通过检测蜗牛家族基因SnA和Slug的变化来进一步表征Twist突变胚胎的特征。也要检查导致遗传性颅缝早闭综合征的其他基因(成纤维细胞生长因子受体和MSX基因)在Twist突变胚胎中的表达是否发生了变化。2.通过产生和分析SnA/Twist双突变来检验这样的假设，即与果蝇一样，Twist和蜗牛家族的基因将在相同的遗传途径中发挥作用。3.利用母鼠蜗牛家族基因slug(slug/twist)产生双突变体并进行分析。

The long term goals of this project are to generate and characterize mouse models of human craniofacial disease syndromes, and to understand the genetic and biochemical pathways underlying these disease syndromes. Craniosynostosis, the premature fusion of the calvarial bones of the skull, is a significant medical problem, occurring in 1 in 3000 live births. The abnormal skull growth associated with craniosynostosis may result in raised intracranial pressure, impaired cerebral blood flow, airway obstruction, impaired vision and hearing learning difficulties and adverse psychological effects. In this proposal, we will study a mouse model for Saethre-Chotzen Syndrome, one of the most common autosomal dominant disorders of craniosynostosis in humans. Haploinsufficiency for the human TWIST gene, which encodes a bHLH-type transcription factor, has been demonstrated to be one of the major causes of Saethre-Chotzen Syndrome. Other familial cases of Saethre-Chotzen Syndrome are caused by mutations in some of the genes encoding fibroblast growth factor receptors (FGR2 and FGR3). A null mutation in the mouse Twist gene results in early embryonic death in homozygotes, and in heterozygotes results in partially penetrant skeletal defects that replicate certain features of Saethre-Chotzen syndrome. The human TWIST gene is a homolog of the Twist gene of Drosophila. Genetic evidence in Drosophila has demonstrated that mutations in the Twist gene interact with mutations in another transcription factor encoded by the Snail gene. We have constructed targeted mutations in two mouse homologs of Snail (termed Sna and Slug). We will test the hypothesis that, as in Drosophila, genes of the Snail and Twist family both function in the same genetic pathway in mice. The specific aims of this proposal are to: 1. Further characterize Twist mutant embryos by testing fro altered expression of the Snail family genes Sna and Slug. Also examine whether expression of other genes responsible for inherited craniosynostosis syndromes (the fibroblast growth factor receptors and the Msx genes) are altered in Twist mutant embryos. 2. Test the hypothesis that, as in Drosophila, genes of the Twist and Snail families will function in the same genetic pathway by generating and analyzing Sna/Twist double mutants. 3. Generate and analyze double mutants with the mother mouse Snail family gene Slug (Slug/Twist double mutants).