Control of retinal angiogenesis by Tbx3

项目概要/摘要 视网膜血管破裂，无论是在发育期间还是在成年期，仍然是导致视网膜病变的主要原因。 失明，但指导其形成和生存的潜在分子机制仍然存在 大部分未知。视网膜神经节细胞（RGC）是最早分化的细胞，表达弥散性的 触发星形胶质细胞和内皮细胞进入视网膜的分子，导致 形成脉管系统。因此，了解转录因子网络表达在 RGCs和内皮细胞对于视网膜血管系统的形成和维持至关重要。我们 研究小组的研究表明，转录因子TBX 3在这一过程中起着关键作用。我们 先前发现TBX 3是青蛙眼睛形成所必需的，但它在哺乳动物眼睛中的作用 形成仍然未知。一个令人困惑的问题是，第一次报告的基因破坏， Tbx 3的基因实际上是一个亚型，具有不完全的催眠状态。因此，为了解决 TBX 3在眼形成中的作用，我们转而分析了一种有效的条件性敲除Tbx 3的方法， 视网膜组织使用这种鼠标，我们有令人信服的初步数据表明需要Tbx 3 用于内在光敏视网膜神经节细胞（ipRGC）的形成并且也由， 并且是正常视网膜内皮细胞形成所必需的。在目标1中，我们将确定 RGC需要TBX 3，我们将对TBX 3转录靶点进行无偏搜索。在 目的2，我们描述了Tbx 3的缺失如何影响内皮细胞中的Wnt信号传导， 内皮细胞需要TBX 3来形成视网膜血管。在完成这项工作后， 探索R21，我们将奠定基础，以确定细胞类型和转录 目标是受Tbx 3损失影响最大的目标，以便未来的实验可以进一步研究关键因素 对于视网膜中的RGC和血管形成是必需的。

Project Summary/Abstract Retinal vascular disruption, either during development or in adulthood, remains a major cause of blindness, yet the underlying molecular mechanisms guiding their formation and survival remain largely unknown. Retinal ganglion cells (RGCs), being the first to differentiate, express diffusible molecules that trigger the entry of astrocytes and endothelial cells into the retina, leading to formation of the vasculature. Thus, understanding the transcription factor network expressed in RGCs and endothelial cells is critical for formation and maintenance of retinal vasculature. Our group has shown that the transcription factor, TBX3, plays a critical role in this process. We previously found that TBX3 is required for eye formation in frog, yet its role in mammalian eye formation remained unknown. A confounding issue was that the first reported genetic disruption of Tbx3 was actually a hypomorph with incomplete penetrance. Thus, to address the role of TBX3 in eye formation, we have turned to analyze a validated conditional knockout of Tbx3 from retinal tissues. Using this mouse, we have compelling preliminary data showing Tbx3 is required for intrinsically photosensitive retinal ganglion cell (ipRGC) formation and is also expressed by, and essential for, normal retinal endothelial cell formation. In Aim 1, we will determine which RGCs require TBX3 and we will perform an unbiased search for TBX3 transcriptional targets. In Aim 2, we characterize how the loss of Tbx3 affects Wnt signaling in endothelial cells and if TBX3 is required by endothelial cells for retinal vasculature formation. At the completion of this exploratory R21, we will have laid the foundation to determine the cell types and transcriptional targets most affected by Tbx3 loss, so that future experiments can further examine key factors essential for RGC and vascular formation in the retina.