THE ROLE OF THE HOMEOBOX SIX3 IN HOLOPROSENCEPHALY/CYCLOPIA

同源框 SIX3 在前脑无裂畸形/独眼畸形中的作用

• 批准号: 7094949
• 负责人: GUILLERMO C OLIVER
• 金额: $ 37.09万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094949
• 关键词: congenital brain disorder; emotions; gene mutation; genes; genetics; human; lead; model; mutant; neural plate /tube; phenotype; proteins; role; zebrafish

DESCRIPTION (provided by applicant): Holoprosencephaly (HPE) is the most common embryologic malformation of the forebrain in humans caused by incomplete cleavage of the prosencephalon. This malformation which affects the development of the prechordal plate and anterior neuroectoderm includes various degrees of midline fusion and cyclopia affecting the forebrain and face. Various genetic factors and environmental agents contribute to the etiology of HPE. In humans, mutations in the SIX3 gene encoding a homeodomain transcription factor have been associated with HPE. The genetic and cellular mechanisms of SIX3-promoted HPE are poorly understood. It remains unclear whether mutant SIX3 proteins have hypomorphic, antimorphic, or neomorphic activity. SIX3 mutations cause HPE in a dominant manner but with variable penetrance and expressivity, a finding that suggests that S/X3 interacts with other genetic loci. Functional inactivation of Six3 in mice has shown that repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development; however, S/x3-heterozygous mice did not exhibit any obvious morphologic alteration. In this application, we propose to employ a combination of genetic, embryologic, and molecular methods to reproduce and characterize the HPE/cyclopia phenotype in mouse and zebrafish. Aim 1 entails in vivo and in vitro molecular and transcriptional characterization of the generated HPE Six3 mutant proteins. Aim 2 will generate zebrafish and mouse models of Six3-mediated HPE. We will use these models to identify tissues and genetic pathways affected by mutant Six3. Aim 3 focuses on the identification of genes that cooperate with mutated Six3 in promoting HPE. These proposed studies will advance our understanding of the signaling pathways affected by HPE-Six3 mutations and, ultimately, will provide additional information to be used with the genetic counseling of human carriers of HPE-SIX3 mutations and decrease the frequency of these birth defects.

描述（由申请人提供）：Holoprosencephaly（HPE）是前脑在人类中最常见的胚胎畸形，这是由于prosencephalon的不完全裂解而引起的。这种影响影响前板和前神经外胚层的发展的畸形包括各种中线融合和环境影响前脑和面部的环境。各种遗传因素和环境药物有助于HPE的病因。在人类中，编码同源域转录因子的Six3基因中的突变与HPE有关。六个促进的HPE的遗传和细胞机制知之甚少。尚不清楚突变体Six3蛋白是否具有肌莫尔，抗态或新生态活性。 SIX3突变以主导方式导致HPE，但具有可变的外观和表达性，这一发现表明S/X3与其他遗传基因座相互作用。小鼠中六3的功能失活表明，抑制前神经外胚层中Wnt信号的抑制对于脊椎动物前脑发育至关重要。但是，S/X3杂合小鼠没有表现出任何明显的形态改变。在此应用中，我们建议采用遗传，胚胎学和分子方法的组合来繁殖和表征小鼠和斑马鱼中的HPE/环皮表型。 AIM 1在体内和体外分子和转录表征中都需要产生的HPE Six3突变蛋白。 AIM 2将生成六十介介导的HPE的斑马鱼和小鼠模型。我们将使用这些模型来识别受突变体63影响的组织和遗传途径。 AIM 3的重点是鉴定在促进HPE中与突变的Six3合作的基因。这些提出的研究将提高我们对受HPE-SIX3突变影响的信号通路的理解，最终将提供其他信息，以与HPE-SIX3突变的人类载体的遗传咨询一起使用，并降低这些先天缺陷的频率。