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: 6898157
• 负责人: ALI H BRIVANLOU
• 金额: $ 27.75万
• 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/6898157
• 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）：该提案涉及TGF β的作用 在脊椎动物中胚层形成中的信号传导。使用 非洲爪蟾胚胎和胚胎外植体的表达背景 克隆，候选基因的方法和微阵列技术，我们有 确定了五个基因，通过调节TGF β途径， 中胚层形成的输入。候选基因的方法导致了 发现LTBP-1是一个组织特异性基因， 具有激活素的所有胚胎功能，包括中胚层和次级 轴感应我建议解决的相互作用的特殊性， LTBP-1与TGF β家族成员，其与组织者的关系 也与激活素结合的特异性抑制剂如卵泡抑素，并探索 相关家族成员LTBP 2和3的功能。功能屏幕的增益 导致了OS 4的发现，OS 4是一个进化上保守的基因， 未知的功能，这也能够诱导中胚层和次生轴。我 我建议将OS 4与信号通路联系起来，首先通过进行上位性 分析TGFB途径中的OS 4，第二通过分离结合 伙伴我们的原型爪蟾微阵列已经识别出大量的 激活素调控的cDNA，包括三个新基因。我建议，首先， 跟踪这些新的胚胎学和生物化学活性， 反应基因第二，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） 它们受到激活素蛋白浓度的不同阈值的调节， 目的是在时间上表征和组织 激活素调控的基因总的来说，这笔赠款的目的将丰富 我们不仅对早期脊椎动物中胚层形成的了解， 关于TGF β途径，这与许多其他生物学领域有关， 胚胎学之外的医学