Role of T-box genes in mouse development

这个项目的长期目标是了解T-box转录因子基因家族的发育作用，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。这项工作从探索基因家族的进化开始，并在哺乳动物基因组中发现了以前未知的基因，最终确定了一个由老鼠和人类共同的17个T-box基因组成的家族。其中一些，凭借它们的染色体位置，是人类发育综合征的候选者，我们通过靶向突变生产小鼠模型的工作验证了这些预测。人类T-box基因的突变随后被发现是DiGeorge、尺骨-乳房、小膝盖骨和Holt-Oram综合征等畸形的基础。 这一提议有两个主要主题：探索T-box基因如何相互作用，以及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定向突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基因的有趣表达模式以及器官系统与重要的人类疾病的相关性，已选择了几个器官系统进行深入研究：先天性心脏病是人类出生第一年死亡的主要原因。至少有4个T-box基因在心脏发育中发挥关键作用，我们将继续单独和联合探索这些基因突变，以了解它们如何促进正常和异常发育。Tbx2和Tbx3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来探索这些角色。在胰岛发育过程中，T-box基因在性腺和外生殖器以及胰腺中的有趣表达模式已经被发现。按照这些研究路线，将发现这些基因的功能作用，以及它们可能分别参与与糖尿病相关的生殖系统或胰腺发育中的先天性出生缺陷。

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.