TGFb Signaling in Vertebrate Mesoderm Induction

脊椎动物中胚层诱导中的 TGFb 信号转导

• 批准号: 7247938
• 负责人: ALI H BRIVANLOU
• 金额: $ 31.18万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247938
• 关键词: Activins; Address; Adult; Amaze; Bilateral; Biochemical; Biological; Biological Assay; C-terminal; Caenorhabditis elegans; Cell Line; Cell Nucleus; Cells; Cocos; Complement Factor B; Development; Disease; Dorsal; Embryo; Embryonic Development; Event; Family; Family member; Funding; Gastrula; Generations; Genes; Germ Layers; Goals; Human; Individual; Knowledge; Life; Malignant Neoplasms; Mammalian Cell; Mesoderm; Molecular; Mutation; Neurula; OS4 Gene; Organogenesis; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation Site; Proteins; Rana; Range; Side; Signal Pathway; Signal Transduction; Snow; Staging; Structure; Substrate Specificity; TGFB1 gene; Tissues; Transforming Growth Factors; Vertebrates; Xenopus; angiogenesis; base; carboxy-terminal domain phosphatase; cell type; developmental disease; expression cloning; in vivo; loss of function; member; neurogenesis; notochord; research study; tumorigenesis; zygote

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the biochemical and embryological function of the Transforming Growth Factor-B (TGF-B) pathway in the induction and patterning of the mesodermal embryonic germ layer in Xenopus. By combining expression cloning in Xenopus embryos, global transcriptional profiling, and biochemical approaches during the last round of funding, we have identified key factors which modulate the TGF-B pathway at multiple levels in the generation of the primary embryonic axis and the establishment of discrete cell fates. Building on this progress, we will focus on two of these factors that are unusual regulators of the TGFB pathway: Coco, acting outside of the cell, and SCP2, the first identified Smad phosphatase, acting in the nucleus. I have two main objectives. The first is to dissect the molecular mechanism underlying the biochemical function of coco in the context of the very early embryo. This will be done by eliminating Coco from the fertilized eggs and assess the consequence of this loss of function on the development of the embryo. In line with this mechanistic analysis, embryonic factors that interact with Coco protein will be identified to unveil Coco-partners. The second aim, targets the unraveling of the biochemical, cellular and embryological function of long awaited players in the TGFB pathway, Smad phosphatases, which we have finally identified. We will also extend this analysis to individual family members of this group by addressing comparatively their biochemical and embryological functions. The TGFB pathway has been evolutionarily conserved from C. elegans to human, covering an amazing range of biological activities both in embryogenesis and adult life. Mutations in this pathway are the causes of various diseases including developmental disorders and human cancer. Therefore, the findings derived from the studies presented in this application extend beyond their relevance to our basic molecular understanding of embryological events, and reach our knowledge about this important signaling pathway, reiterated again and again in different tissues and cell type throughout life.

描述（由申请人提供）：本提案的总体目标是阐明转化生长因子-B（TGF-B）途径在非洲爪蟾中胚层诱导和形成模式中的生化和胚胎学功能。通过结合表达克隆在非洲爪蟾胚胎，全球转录谱，和生化方法在最后一轮的资金，我们已经确定了关键因素，调节TGF-β通路在多个层面上的产生的主要胚胎轴和建立离散的细胞命运。基于这一进展，我们将重点关注TGFB通路的两个不寻常的调节因子：Coco，作用于细胞外，以及SCP 2，第一个确定的Smad磷酸酶，作用于细胞核。我有两个主要目标。第一个是在非常早期的胚胎背景下剖析可可的生化功能的分子机制。这将通过从受精卵中消除可可来完成，并评估这种功能丧失对胚胎发育的影响。根据这一机制分析，将确定与可可蛋白相互作用的胚胎因素，以揭示可可伴侣。第二个目标是解开TGFB通路中期待已久的参与者Smad磷酸酶的生化，细胞和胚胎学功能，我们最终确定了这些酶。我们还将通过比较其生化和胚胎学功能，将这种分析扩展到该组的单个家族成员。TGFB途径在进化上与C.从线虫到人类，涵盖了胚胎发育和成年生活中惊人的生物学活动。该途径中的突变是各种疾病的原因，包括发育障碍和人类癌症。因此，从本申请中提出的研究中得出的发现超出了它们与我们对胚胎学事件的基本分子理解的相关性，并达到了我们对这一重要信号通路的认识，在整个生命中在不同组织和细胞类型中一次又一次地重申。