Role of T-box genes in mouse development

该项目的长期目标是了解转录因子基因的T-box家族的发育作用，以及它们在器官发生过程中如何相互作用和影响信号通路。这项工作始于对基因家族进化的探索，以及在哺乳动物基因组中发现以前未知的基因，最终定义了一个由17个小鼠和人类共有的T-box基因组成的家族。其中一些，凭借其染色体位置，是人类发育综合征的候选人，我们的工作产生小鼠模型的靶向诱变验证了这些预测。随后发现人类T盒基因突变是DiGeorge、尺骨-乳房、小髌骨和Holt-Oram综合征等异常的基础。 这个建议有两个主要主题：探索T-box基因如何相互作用，并了解它们如何通过不同的信号通路指导器官发生。为了实现这些目标，我们将利用我们实验室通过靶向诱变产生或正在产生的简单和条件突变以及来自其他实验室的突变。由于T-box基因表达的有趣模式以及器官系统与重要人类疾病的相关性，已经选择了几个器官系统进行深入研究：先天性心脏缺陷是人类生命第一年死亡的主要原因。至少有4个T-box基因在心脏发育中起着关键作用，我们将继续探索这些基因突变的单独和组合，以了解它们如何促进正常和异常发育。Tbx 2和Tbx 3在早期乳腺发育过程中相互作用，并与乳腺癌有关。我们将继续使用条件等位基因探索这些作用。有趣的表达模式的T-box基因已被发现在性腺和外生殖器，也在胰岛发育过程中的胰腺。这些调查将遵循这些基因的功能作用，并分别发现它们可能参与生殖系统先天性出生缺陷或与糖尿病相关的胰腺发育。

The long-term objective of this project is to understand the developmental roles of the T-box family of transcription factor genes and how they interact and impinge on signaling pathways during organogenesis. The work started with an exploration of the evolution of the gene family and the discovery of previously unknown genes in the mammalian genome, eventually defining a family of 17 T-box genes common to mouse and human. A number of these, by virtue of their chromosomal locations, were candidates for human developmental syndromes and our work producing mouse models by targeted mutagenesis validated these predictions. Mutations in human T-box genes were subsequently found to underlie anomalies such as DiGeorge, ulnar-mammary, small patella and Holt-Oram syndromes. There are two main themes to this proposal: to explore how T-box genes interact and to understand how they direct organogenesis through different signaling pathways. To accomplish these goals, we will make use of simple and conditional mutations produced or being produced in our laboratory by targeted mutagenesis as well as mutations from other labs. Several organ systems have been chosen for in-depth study due to interesting patterns of expression of T-box genes and the relevance of the organ systems to important human diseases: Congenital heart defects are a leading cause of death in humans during the first year of life. At least 4 T-box genes play critical roles in heart development and we will continue to explore these gene mutations individually and in combination to understand how they contribute to normal and abnormal development. Tbx2 and Tbx3 interact during early mammary gland development and are implicated in breast cancers. We will continue to explore these roles using conditional alleles. Interesting expression patterns of T-box genes have been uncovered in the gonads and external genitalia and also in the pancreas during islet development. These lines of investigation will be followed to discover the functional role of these genes and their possible involvement in congenital birth defects in the reproductive system or pancreas development relevant to diabetes, respectively.