A GENETIC PATHWAY REQUIRED FOR PHARYNGEAL ARCH DEVELOPME

咽弓发育所需的遗传途径

• 批准号: 6458336
• 负责人: ANTONIO BALDINI
• 金额: $ 14.75万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6458336
• 关键词: developmental disease /disorder; developmental genetics; embryogenesis; embryonic stem cell; endoderm; gene expression; gene mutation; gene targeting; genetically modified animals; laboratory mouse; pharynxs

DESCRIPTION (provided by applicant): Functional analysis of the murine chromosomal segment, homologous to the human region deleted in DiGeorge syndrome, identified a putative transcription factor, Tbx1, required for the development of the pharyngeal apparatus. Homozygous mutation of Tbx1 leads to severe disruption of pharyngeal arches 1-2, and absence of pharyngeal arches 3-6. The pharynx lacks the characteristic segmented pattern to assume a tube-like morphology. On the basis of the mutant phenotype, we hypothesize that Tbx1 has multiple roles in the development of the pharyngeal apparatus. This hypothesis cannot be addressed with the current germ-line mutation model because the early requirement of Thx 1 prevents us from testing gene function later in development. To address our hypothesis we propose to develop and test an in vivo conditional system for positive and negative regulation of Tbx1 expression. First we will construct and test the system, and subsequently, we will establish the temporal requirement of Tbx1 expression, and the role of Thx 1 after the initial pharyngeal endoderm patterning. Tbx1 mutants present one of the most dramatic and yet specific pharyngeal phenotypes so far reported. The strategy proposed here is intended to address a broad range of questions concerning the development of the pharyngeal apparatus. This is because the tools generated will allow us to modulate the development of this complex structure. Developmental problems of the pharyngeal apparatus underlie many birth defects, including relatively common craniofacial and cardiovascular abnormalities.

描述（由申请人提供）：小鼠的功能分析 染色体片段，与 DiGeorge 中删除的人类区域同源 综合征，确定了一个假定的转录因子 Tbx1，这是 咽器的发育。 Tbx1 的纯合突变导致 咽弓 1-2 严重破坏，咽弓消失 3-6.咽部缺乏特征性分段模式来假设 管状形态。根据突变表型，我们假设 Tbx1 在咽部发育中具有多种作用。这 目前的种系突变模型无法解决这一假设 因为Thx 1的早期要求阻止我们测试基因功能 后期开发中。为了解决我们的假设，我们建议开发和测试 Tbx1 正向和负向调节的体内条件系统 表达。首先，我们将构建并测试系统，然后，我们 将确定 Tbx1 表达的时间要求以及 Thx 的作用 1 初始咽内胚层图案形成后。 Tbx1 突变体呈现出最引人注目但又最特殊的咽部突变体之一 迄今为止报道的表型。这里提出的策略旨在解决 有关咽部发育的广泛问题 设备。这是因为生成的工具将允许我们调节 这种复杂结构的发展。咽部发育问题 装置是许多出生缺陷的基础，包括相对常见的颅面部缺陷 和心血管异常。