BMP signaling in vertebrate development

描述(申请人提供)：骨形态发生蛋白(BMP)是分泌信号分子的转化生长因子超家族的成员。BMP信号是一条古老的途径，甚至可以在海绵动物门的成员中找到。BMPs在进化中的作用是不同的，包括控制成体的配子发生、早期胚胎发育、细胞分化/凋亡和组织内环境的稳定。BMP信号从细胞外环境、受体到细胞核的调控机制已经取得了很大的进展。这一认识导致了“核心”途径的概念，该途径介导BMP信号转导来控制靶基因的表达。然而，关于这一核心途径如何在不同类型的细胞和发育过程中的不同时间引起不同的反应，我们仍然知之甚少。缺乏这种知识的一个原因是，直到最近，我们还没有方法来研究BMP如何在全基因组水平上直接影响基因。第二个原因是，虽然我们已经深入了解了细胞内BMP介导物Smads如何识别他们的基因靶标，但似乎Smads靶向基因也需要与其他转录因子相互作用。目前尚不清楚这些伙伴蛋白是在逐个基因的基础上发挥功能，还是具有更广泛的功能来控制整个BMP反应基因网络。我们最近提供的证据表明，进化上保守的果蝇基因SchNurri的同源基因编码一个共同的伙伴，可能更广泛地用于促进BMP靶基因识别。我们的假设和模型基于以下关键的最新发现：1.我们已经确定了一个核心的BMP反应元件(BRE)，它特异性地响应从果蝇到非洲爪哇、斑马鱼和小鼠的BMP信号。2.非洲爪哇BRE报告基因实验表明，骨形态发生蛋白信号不仅在中胚层和外胚层活跃，而且在内胚层也是如此。3.Affymetrix基因芯片表明，内胚层骨形态发生蛋白信号激活了一个核心基因网络，该网络也在另外两个胚层中被诱导。4.我们发现了一种关键的系统发育保守的转录因子(施努里相关锌指蛋白)，它通过BRE介导骨形态发生蛋白信号。我们建议解决以下几个具体目标：1.骨形态发生蛋白信号在内胚层基因调控网络中的作用(S)2.骨形态发生蛋白信号网络在胚胎发生中的作用

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