TGFBeta Signaling in Vertebrate Mesoderm Induction

脊椎动物中胚层诱导中的 TGFBeta 信号转导

• 批准号: 6603402
• 负责人: ALI H BRIVANLOU
• 金额: $ 29.24万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603402
• 关键词: Xenopus; antibody; binding proteins; biological signal transduction; complementary DNA; embryogenesis; follistatin; gene expression; immunoprecipitation; inhibin; ligands; mesoderm; microarray technology; regulatory gene; transforming growth factors; vertebrate embryology

DESCRIPTION (provided by applicant): This proposal addresses the role of TGFbeta signaling in the formation of the vertebrate mesodermal germ layer. Using Xenopus laevis embryos and embryonic explants in the context of expression cloning, candidate gene approaches and microarray technology, we have identified five genes which, by modulating the TGFbeta pathway provide a strong input in mesoderm formation. The candidate gene approach has lead to the discovery that LTBP-1 is an organizer specific gene which binds and synergizes with all the embryonic functions of activin, including mesoderm and secondary axis induction. I propose to address the specificity of the interaction of LTBP-1 with members of the TGFbeta family, its relationship with organizer specific inhibitors which also bind to activin such as follistatin, and explore the functions of related family members LTBP2 and 3. A gain of function screen has led to the discovery of OS4, an evolutionarily conserved gene of previously unknown function, which is also able to induce mesoderm and secondary axis. I propose to link OS4 to a signaling pathway(s), first by performing an epistatic analysis of OS4 in the TGFB pathway, and second by isolation of binding partners. Our prototype Xenopus microarrays have identified a large number of activin-regulated cDNAs, including three novel genes. I propose, first, to follow on the embryological and biochemical activities of these novel responsive genes. Second, I propose the use of a 5000 gene array available in my laboratory to globally identify genes (including immediate early response) that are regulated by different thresholds of activin protein concentration, with the aim of characterizing and organizing temporally the repertoire of genes regulated by activin. Taken together, the aims of this grant will enrich our knowledge not only about early vertebrate mesoderm formation, but also about the TGFBeta pathway, which is relevant to many other areas of biology and medicine beyond embryology.

描述（由申请人提供）：该提案阐述了 TGFbeta 的作用 脊椎动物中胚层胚层形成中的信号传导。使用 表达背景下的非洲爪蟾胚胎和胚胎外植体 克隆、候选基因方法和微阵列技术，我们有 确定了五个基因，通过调节 TGFbeta 途径提供了强大的 输入中胚层形成。候选基因方法已导致 发现 LTBP-1 是组织者特异性基因，可结合并协同作用 具有激活素的所有胚胎功能，包括中胚层和次级 轴感应。我建议解决相互作用的特殊性 LTBP-1与TGFbeta家族成员及其与组织者的关系 也与激活素结合的特异性抑制剂，例如卵泡抑素，并探索 相关家族成员 LTBP2 和 3 的功能。功能屏幕的增益 导致了 OS4 的发现，这是以前的进化保守基因 功能未知，也能诱导中胚层和次轴。我 建议首先通过执行上位性将 OS4 与信号传导通路连接起来 分析 TGFB 途径中的 OS4，然后分离结合 合作伙伴。我们的原型爪蟾微阵列已鉴定出大量 激活素调节的 cDNA，包括三个新基因。我建议首先 跟踪这些新颖的胚胎学和生化活性 反应基因。其次，我建议使用 5000 个基因阵列 我的实验室在全球范围内识别基因（包括立即早期反应） 由激活素蛋白浓度的不同阈值调节， 目的是暂时描述和组织曲目 受激活素调节的基因。总而言之，这笔赠款的目的将丰富 我们的知识不仅关于早期脊椎动物中胚层的形成，而且 关于 TGFBeta 途径，该途径与生物学的许多其他领域相关 超越胚胎学的医学。