ANIMAL MODELS FOR SAETHRE CHOTZEN SYNDROME

该项目的长期目标是生成和表征人类颅面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。颅缝早闭，即颅骨的颅骨过早融合，是一个重大的医学问题，每 3000 名活产儿中就有 1 人发生颅缝早闭。与颅缝早闭相关的颅骨生长异常可能导致颅内压升高、脑血流受损、气道阻塞、视力和听力受损、学习困难以及不良心理影响。在本提案中，我们将研究 Saethre-Chotzen 综合征的小鼠模型，该综合征是人类最常见的常染色体显性遗传性颅缝早闭症之一。编码 bHLH 型转录因子的人类 TWIST 基因的单倍体不足已被证明是 Saethre-Chotzen 综合征的主要原因之一。 Saethre-Chotzen 综合征的其他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 基因的无效突变会导致纯合子的早期胚胎死亡，而杂合子则会导致部分渗透性骨骼缺陷，从而复制 Saethre-Chotzen 综合征的某些特征。人类 TWIST 基因是果蝇 Twist 基因的同源物。果蝇的遗传证据表明，Twist 基因的突变与 Snail 基因编码的另一个转录因子的突变相互作用。我们在 Snail 的两种小鼠同源物（称为 Sna 和 Slug）中构建了靶向突变。我们将测试这样一个假设：就像在果蝇中一样，Snail 和 Twist 家族的基因在小鼠中都在相同的遗传途径中发挥作用。该提案的具体目标是： 1. 通过测试 Snail 家族基因 Sna 和 Slug 表达的改变，进一步表征 Twist 突变体胚胎。还检查 Twist 突变胚胎中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）的表达是否发生改变。 2. 通过生成和分析 Sna/Twist 双突变体，检验以下假设：与果蝇一样，Twist 和 Snail 家族的基因将在相同的遗传途径中发挥作用。 3. 用母鼠Snail家族基因Slug生成并分析双突变体（Slug/Twist双突变体）。

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).