Regulation and molecular function of the T-box transcription factors Tbx2 and Tbx3 in the development of the murine lung

脊椎动物器官的发育依赖于相邻组织区室中增殖速率和分化模式的精确时空编排。在胚胎肺的分支形态发生过程中，从上皮内胚层分支尖端分泌的许多信号将下面的间充质维持在未分化的增殖状态，这反过来又是维持远端肺芽上皮中的前体细胞所需的，并允许继续生长。尽管在包括肺在内的许多器官的发育中已经确定了维持前体组织增殖的单个信号，但仍然不清楚这些信号如何整合并转化为细胞周期控制。我们最近的工作表明，T-box转录抑制因子Tbx 2通过直接抑制细胞周期抑制基因Cdkn 1a和Cdkn 1b来维持肺间质的增殖并抑制其分化。我们额外的初步工作表明，Tbx 2和密切相关的Tbx 3整合各种上皮信号，抑制间充质中的一组不同的抗增殖基因活性。因此，我们希望确定Tbx 2和Tbx 3的上游调控模块和下游效应器在发展中的lun中。分析Tbx 2和Tbx 3在肺间充质中表达的调控我们希望确定诱导和/或维持Tbx 2/Tbx 3表达的信号通路（Shh、Wnt、Bmp和Tgf）在时间和空间上的单独和组合活性，并表征Tbx 2/Tbx 3功能对肺中这些信号通路活性的贡献.肺间质Tbx 2/Tbx 3分子功能分析我们希望进一步表征缺乏Tbx 2、Tbx 3和Tbx 2/Tbx 3的胚胎肺和过表达Tbx 2的成人肺中的分子和细胞变化，分析Wnt、Bmp和干扰素信号传导/干扰素调节因子作为Tbx 2/Tbx的下游效应物的作用，并鉴定和表征Tbx 2和Tbx 3在该组织中的直接靶点。我期望从这些实验中新的见解的监管网络，保持分支形态发生在发展中的肺和复杂的增殖和分化途径的Tbx 2/Tbx 3调节肺间质。这种见解也可能有助于更好地理解Tbx 2和Tbx 3在许多癌症中上调的意义。

Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. During branching morphogenesis of the embryonic lung, a number of signals secreted from the epithelial endodermal branch tips maintain the underlying mesenchyme in an undifferentiated proliferative state which in turn is required to maintain precursor cells in the distal lung bud epithelium, and allow continued outgrowth. Although individual signals that maintain proliferation of precursor tissues have been identified in the development of many organs, including the lung, it has remained unclear how these signals are integrated and translated into cell-cycle control. Our recent work has shown that the T-box transcriptional repressor Tbx2 maintains proliferation and inhibits differentiation of the pulmonary mesenchyme by directly repressing the cell-cycle inhibitor genes Cdkn1a and Cdkn1b. Our additional preliminary work suggests that Tbx2 and the closely related Tbx3 integrate various epithelial signals to repress a diverse set of anti-proliferative gene activities in the mesenchyme. Therefore, we wish to define the upstream regulatory modules and the downstream effectors of Tbx2 and Tbx3 in the developing lunThe specific aims of this proposal are:1. Analysis of the control of Tbx2 andTbx3 expression in the lung mesenchyme.We wish to determine the individual and combined activities of signaling pathways (Shh, Wnt, Bmp and Tgfß) that induce and/or maintain expression of Tbx2/Tbx3 in time and space, and characterize the contribution of Tbx2/Tbx3 function to these signaling activities in the lung.2. Analysis of the molecular function of Tbx2/Tbx3 in the lung mesenchyme. We wish to further characterize the molecular and cellular changes in embryonic lungs lacking Tbx2, Tbx3 and Tbx2/Tbx3, and in adult lungs overexpressing Tbx2, analyze the role of Wnt, Bmp and interferon signaling/interferon regulatory factors as downstream effectors of Tbx2/Tbx, and identify and characterize direct targets of Tbx2 and Tbx3 in this tissue. I expect from these experiments new insight into the regulatory network that maintains branching morphogenesis in the developing lung and into the complexity of the proliferative and differentiation pathways regulated by Tbx2/Tbx3 in the pulmonary mesenchyme. This insight might also be useful to better understand the significance of upregulation of Tbx2 and Tbx3 in a number of cancers.