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.

前脑无裂畸形 (HPE) 是人类最常见的前脑胚胎畸形 由于前脑的不完全分裂。这种畸形会影响孩子的发育 脊索前板和前神经外胚层包括不同程度的中线融合和独眼 影响前脑和面部。多种遗传因素和环境因素导致病因 慧与的。在人类中，编码同源域转录因子的 SIX3 基因发生突变 与慧与相关。 SIX3 促进的 HPE 的遗传和细胞机制尚不清楚。它 目前尚不清楚突变的 SIX3 蛋白是否具有亚态、反态或新态活性。六3 突变以显性方式导致 HPE，但外显率和表现力各不相同，这一发现 表明 S/X3 与其他基因位点相互作用。 Six3 在小鼠体内的功能失活表明 前神经外胚层 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。在这个应用程序中，我们 提议采​​用遗传、胚胎学和分子方法的结合来繁殖和 表征小鼠和斑马鱼的 HPE/独眼动物表型。目标 1 需要体内和体外 生成的 HPE Six3 突变蛋白的分子和转录特征。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组织 和'受突变体 Six3 影响的遗传途径。目标 3 侧重于识别合作基因 与突变的 Six3 一起促进 HPE。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，最终将提供更多信息 与 HPE-SIX3 突变人类携带者的遗传咨询一起使用，并降低 HPE-SIX3 突变的频率 这些出生缺陷。