A GENETIC PATHWAY REQUIRED FOR PHARYNGEAL ARCH DEVELOPME

描述（由申请方提供）：鼠源性免疫缺陷病毒的功能分析 染色体片段，与DiGeorge中缺失的人类区域同源 综合征，确定了一个假定的转录因子，Tbx 1，所需的 咽器的发育。Tbx 1的纯合突变导致 咽弓1-2严重断裂，咽弓缺失 3-6.咽部缺乏特征性的分段模式， 管状形态。根据突变表型，我们假设， Tbx 1在咽器的发育中具有多种作用。这 目前的生殖系突变模型无法解决这一假设 因为Thx 1的早期需求阻碍了我们检测基因功能 后来发展。为了解决我们的假设，我们建议开发和测试 用于Tbx 1的正和负调节的体内条件系统 表情首先，我们将构建和测试系统，然后，我们 将建立Tbx 1表达的时间要求，以及Thx 1在最初的咽内胚层图案化之后。 tbx 1突变体呈现出一种最戏剧性的，但具体的咽 目前报道的表型。这里提出的战略旨在解决 关于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整 这种复杂结构的发展。咽部发育问题 器官是许多出生缺陷的基础，包括相对常见的颅面 和心血管异常

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.