BMP signaling in vertebrate development

描述（由申请人提供）：骨形态发生蛋白（BMPs）是TGF¿分泌信号分子超家族的成员。BMP信号是一种古老的途径，甚至可以在多孔门（海绵）的成员中发现。bmp在进化中的作用不同，包括控制配子体发生、早期胚胎发育、细胞分化/凋亡和成人组织稳态。在细胞外环境下，配体通过受体进入细胞核的BMP信号传导机制的研究取得了很大进展。这一知识导致了介导BMP信号转导以控制靶基因表达的“核心”途径的概念。然而，对于这一核心通路如何在不同细胞类型和不同发育时期引发不同的反应，我们仍然知之甚少。缺乏知识的一个原因是，直到最近，我们还没有办法在全基因组水平上检查bmp如何直接影响基因。第二个原因是，虽然我们已经深入了解了细胞内BMP介质Smads如何识别其基因靶标，但Smads靶向基因似乎也需要与其他转录因子相互作用。目前尚不清楚这些伴侣蛋白是在基因的基础上起作用，还是具有更广泛的功能来控制BMP反应基因的整个网络。我们最近提供的证据表明，进化上保守的果蝇基因schnurri同源物编码了一个共同的伙伴，可能更广泛地用于促进BMP靶基因的识别。我们的假设和模型是基于以下重要的近期发现：我们已经确定了一个核心BMP响应元件（BRE），该元件对从果蝇到爪蟾、斑马鱼和小鼠的BMP信号做出特异性响应。2. 在爪蟾中进行的BRE报告基因实验表明，BMP信号不仅活跃于中胚层和外胚层，而且还活跃于内胚层。Affymetrix基因芯片表明，内胚层BMP信号激活的核心基因网络也在其他两个胚层中被诱导。我们已经确定了一个关键的系统发育保守转录因子（Schnurri相关锌指蛋白）通过BRE介导BMP信号传导。我们提出以下具体目标：BMP信号在内胚层基因调控网络中的作用胚胎发生过程中schnurri介导的BMP信号传导公共卫生相关性：虽然对BMP信号传导的分子机制的研究仍然是发育生物学的主要焦点，但我们对BMP如何实现其生物学效应的理解仍然非常有限，特别是在转录因子介导的靶基因激活水平上，以及靶基因如何发挥作用。由于BMP信号是动物进化过程中高度保守且广泛使用的发育信号系统，揭示这些过程的基因调控机制具有广泛的影响。此外，调节BMP信号的基因突变会导致各种疾病（如青少年息肉病综合征、原发性肺动脉高压、科登综合征）和发育异常。确定候选基因和信号成分将有助于开发新的诊断和治疗方法。

DESCRIPTION (provided by applicant): Bone morphogenetic proteins (BMPs) are members of the TGF¿ superfamily of secreted signaling molecules. BMP signaling is an ancient pathway and can even be found in members of the phylum Porifera (sponges). The roles of BMPs have diverged in evolution and include the control of gametogenesis, early embryonic development, cell differentiation/apoptosis, and tissue homeostasis in the adult. Great progress has been made on the mechanisms controlling BMP signaling from the ligands in the extracellular environment, through their receptors and into the nucleus. This knowledge has led to the concept of a "core" pathway that mediates BMP signal transduction to control target gene expression. However, we still know relatively little regarding how this core pathway elicits different responses in different cell types and at different times during development. One reason for this lack of knowledge is that we have not, until recently, had methods to examine how BMPs directly impact genes on a genome-wide level. A second reason is that while we have gained insights into how the intracellular BMP mediators, the Smads, recognize their gene targets, it seems that targeting of genes by the Smads also requires interactions with other transcription factors. It is presently unclear whether these partner proteins function on a gene-by-gene basis or have more broad functions to control whole networks of BMP response genes. We have recently provided evidence that the evolutionarily conserved orthologs of the Drosophila gene schnurri encode a common partner that may be used more widely to promote BMP target gene recognition. Our hypotheses and models are based on the following critical recent findings: 1. we have identified a core BMP-responsive element (BRE) that responds specifically to BMP signaling from Drosophila to Xenopus, zebrafish and mouse. 2. BRE reporter gene experiments in Xenopus reveal that BMP signaling is not only active in the mesoderm and ectoderm, as is well known, but also in the endoderm 3. Affymetrix gene chips suggest that endodermal BMP signaling activates a core gene network also induced in the other two germ layers 4. We have identified a critical phylogenetically-conserved transcription factor (Schnurri- related zinc finger protein) mediating BMP signaling through the BRE We propose to address the following specific aims: 1. Role(s) of BMP signaling in endodermal gene regulatory networks 2. Schnurri-mediated BMP signaling during embryogenesis 3. Elucidation of a BMP signaling network PUBLIC HEALTH RELEVANCE: While study of the molecular mechanisms governing BMP signaling remains a major focus of developmental biology, we still have a very limited understanding of how BMPs achieve their biological effects, particularly at the level of transcription factors mediated target gene activation, and how the target genes function. Because BMP signaling is a highly conserved and widely- used developmental signaling systems in animal evolution, uncovering the gene regulatory mechanisms governing these processes has broad impact. Additionally, mutations in genes regulating BMP signaling cause various diseases (e.g., juvenile polyposis syndrome, primary pulmonary hypertension, Cowden's syndrome) and developmental abnormalities. Identification of candidate genes and signaling components will aid in developing new diagnosis and treatments.