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前脑完整畸形(HPE)是人类最常见的前脑胚胎畸形。 由不完全的前脑分裂造成的。这种畸形会影响心脏的发育 前脊索板和前神经外胚层包括不同程度的中线融合和睫状视 影响前脑和面部。各种遗传因素和环境因素在病因中起作用 HPE的。在人类中,编码同源结构域转录因子的Six3基因的突变已经 与HPE相关联。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蛋白是否具有低形态、抗形态或新形态活性。六个3 突变以显性方式引起HPE,但具有不同的外显性和表现性,这一发现 提示S/X3与其他遗传座位存在交互作用。小鼠体内Six3的功能失活表明 在脊椎动物的前脑发育中,Wnt信号在前神经外胚层中的抑制是必不可少的; 而S/x3杂合子小鼠未表现出明显的形态改变。在此应用程序中,我们 建议采用遗传学、胚胎学和分子生物学的组合方法来繁殖和 研究小鼠和斑马鱼的HPE/旋毛症表型。目标1包括体内和体外 所产生的HPE Six3突变蛋白的分子和转录特性。目标2将 建立Six3介导的斑马鱼和小鼠HPE模型。我们将使用这些模型来识别组织 以及受突变体Six3影响的遗传途径。目标3侧重于识别协同作用的基因 突变的Six3在促进HPE中的作用。这些建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 与人类HPE-Six3突变携带者的遗传咨询一起使用,并降低 这些先天缺陷。
英文摘要
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.
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11th Latin American Society for Developmental Biology (LASDB) Conference
Mitochondrial respiration as a regulator of lymphatic cell fate and therapeutic lymphangiogenesis
Functional roles of lymphatics in organogenesis and tissue repair
Functional roles of lymphatics in organogenesis and tissue repair
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