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: 7387386
• 负责人: GUILLERMO C OLIVER
• 金额: $ 34.31万
• 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/7387386
• 关键词: Address; Affect; Anterior; Biochemical; Candidate Disease Gene; Congenital Abnormality; Defect; Development; Disease; Etiology; Exhibits; Face; Forebrain Development; Frequencies; Generations; Genes; Genetic; Genetic Counseling; Holoprosencephaly; Homeobox; Human; In Vitro; Lead; Mediating; Mental Retardation; Mesoderm; Messenger RNA; Methods; Modeling; Molecular; Mus; Mutate; Mutation; Neuroectoderm; Other Genetics; Pathway interactions; Penetrance; Persons; Phenotype; Process; Prosencephalon; Proteins; Repression; Role; Severities; Signal Pathway; Signal Transduction; Six3 protein; Testing; Tissues; Zebrafish; environmental agent; homeodomain; in vivo; loss of function; malformation; mouse model; mutant; neural plate; postnatal; transcription factor

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.

全脑脑（HPE）是人类前脑中最常见的胚胎学畸形 通过不完整的Prosencephalon分裂。这种影响影响发展的畸形 预教板和前神经外胚层包括各种程度的中线融合和环形 影响前脑和脸部。各种遗传因素和环境因素有助于病因 HPE。在人类中，编码同源域转录因子的63基因中的突变已经 与HPE相关。六个促进的HPE的遗传和细胞机制知之甚少。它 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。六 突变以主导方式导致HPE，但具有可变的外观和表现力，这一发现是 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信号传导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。在此应用程序中，我们 建议采用遗传，胚胎学和分子方法的组合来再现和 表征小鼠和斑马鱼中的HPE/环皮表型。目标1在体内和体外需要 生成的HPE SIX3突变蛋白的分子和转录表征。 AIM 2意志 生成六介导的HPE的斑马鱼和小鼠模型。我们将使用这些模型识别组织 和受突变体六号影响的属性途径。 AIM 3专注于合作基因的识别 在促进HPE方面突变了63。这些拟议的研究将提高我们对 受HPE-SIX3突变影响的信号通路，最终将提供其他信息 与HPE-SIX3突变的人类载体的遗传咨询一起使用，并降低 这些出生缺陷。