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）：前脑无裂畸形（HPE）是人类最常见的前脑胚胎畸形，由前脑分裂不完全引起。这种影响脊索前板和前神经外胚层发育的畸形包括不同程度的中线融合和影响前脑和面部的独眼。 HPE 的病因有多种遗传因素和环境因素。在人类中，编码同源域转录因子的 SIX3 基因突变与 HPE 相关。 SIX3 促进的 HPE 的遗传和细胞机制尚不清楚。目前尚不清楚突变型 SIX3 蛋白是否具有亚态、反态或新态活性。 SIX3 突变以显性方式导致 HPE，但外显率和表达率不同，这一发现表明 S/X3 与其他基因位点相互作用。小鼠中 Six3 的功能失活表明，前神经外胚层中 Wnt 信号传导的抑制对于脊椎动物前脑发育至关重要。然而，S/x3杂合子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、胚胎学和分子方法相结合的方法来重现和表征小鼠和斑马鱼的 HPE/独眼动物表型。目标 1 需要对生成的 HPE Six3 突变蛋白进行体内和体外分子和转录表征。目标 2 将生成 Six3 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 Six3 影响的组织和遗传途径。目标 3 侧重于识别与突变 Six3 协同促进 HPE 的基因。这些拟议的研究将增进我们对受 HPE-Six3 突变影响的信号通路的理解，并最终提供更多信息，用于 HPE-SIX3 突变人类携带者的遗传咨询，并降低这些出生缺陷的发生率。