EGFR/ErbB SIGNALING IN LIMB PATTERNING

肢体模式中的 EGFR/ErbB 信号转导

• 批准号: 7799826
• 负责人: Caroline N Dealy
• 金额: $ 23.06万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7799826
• 关键词: Address; Cell Survival; DTR gene; Defect; Distal; Dominant-Negative Mutation; Dorsal; EGF gene; ERBB2 gene; Epidermal Growth Factor Receptor; Epiregulin; ErbB Receptor Family Protein; ErbB4 gene; Event; Family; Family member; Fibroblast Growth Factor; Gene Silencing; Genes; Genetic; Goals; Image; In Vitro; Individual; Joints; Ligands; Limb Bud; Limb Development; Limb structure; Masks; Mediating; Mediator of activation protein; Mesoderm; Morphogenesis; Mus; Pattern; Play; Polydactyly; Progress Reports; Receptor Protein-Tyrosine Kinases; Retroviral Vector; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure; Syndactyly; Tissues; Transforming Growth Factor alpha; Transgenic Mice; epigen; gain of function; implantation; inhibitor/antagonist; insight; loss of function; member; promoter; receptor; response

The goal of this project is to explore the roles of ErbB signaling in limb patterning. The ErbB family consists of ErbB1 (also known as epidermal growth factor receptor or EGFR); three other receptors (ErbB2-4); and 11 ligands. The ErbB signaling network is considered a paradigm for diversification of cell signal responses, as distinct signals are generated by formation of ErbB heterodimers and activation by multiple ligands. Moreover, the ErbB signaling network plays an important role as a central convergence point for multiple signaling pathways, integrating signals emanating from other receptor classes. ErbB1, ErbB4 and the ligands EGF, TGF-alpha and Nrg1 are expressed in chick limbs in fashions consistent with patterning roles. We have found that expression of activated ErbB1 causes limb defects including mirror-image polydactyly, ectopic AERs, duplicated dorsal structures and syndactyly, suggesting ErbB1 may be involved in AP and DV patterning, AER formation, and interdigital regression. We have also found that expression of a dominant negative ErbB, which inhibits signals from multiple ErbBs including ErbB4 but not ErbB1, causes limb defects including loss of distal structures, indicating that an endogenous ErbB other than ErbB1 is important for limb patterning. We will employ multiple gain and loss of function approaches to investigate the roles of ErbB1, ErbB4 and their ligands in mediating limb patterning events, using in chick limbs retroviral vectors, and in mouse limbs, limb tissue-specific promoters. We will explore the activation of intracellular signaling cascades, formation of ErbB heterodimers, and regulatory relationships with other limb patterning signals such as Shh, FGF, Wnt, BMP, and IGF. Since ErbB2 and ErbBS are also expressed in the limb, to gain insight into roles for other ErbBs, and to address potential functional redundancy among ErbB members, we will inhibit multiple ErbBs simultaneously in the limb. These studies should provide insight into the previously unappreciated role of the ErbB signaling network as a key regulator of limb morphogenesis.

本项目的目标是探索ErbB信号在肢体模式中的作用。ErbB家族由ErbB 1（也称为表皮生长因子受体或EGFR）;三种其他受体（ErbB 2 -4）和11种配体组成。ErbB信号网络被认为是细胞信号应答多样化的范例，因为不同的信号是通过ErbB异二聚体的形成和多配体的激活产生的。此外，ErbB信号传导网络作为多个信号传导途径的中心汇聚点发挥重要作用，整合来自其他受体类别的信号。ErbB 1、ErbB 4和配体EGF、TGF-α和Nrg 1在鸡肢中以与模式化作用一致的方式表达。我们发现，ErbB 1的活化表达导致肢体缺陷，包括镜像多指畸形， 异位AER、重复的背侧结构和并指畸形，提示ErbB 1可能参与AP和DV模式、AER形成和趾间退化。我们还发现，显性负性ErbB的表达，抑制来自多种ErbB的信号，包括ErbB 4，但不是ErbB 1，导致肢体缺陷，包括远端结构的损失，表明内源性ErbB而不是ErbB 1是重要的肢体图案。我们将采用多种获得和功能丧失的方法来研究ErbB 1，ErbB 4及其配体在介导肢体图案形成事件中的作用，在鸡肢体逆转录病毒载体中使用，在小鼠肢体中使用肢体组织特异性启动子。我们将探讨细胞内信号级联的激活，ErbB异源二聚体的形成，以及与其他肢体图案信号的调节关系 如Shh、FGF、Wnt、BMP和IGF。由于ErbB 2和ErbBS也在肢体中表达，为了深入了解其他ErbB的作用，并解决ErbB成员之间的潜在功能冗余，我们将在肢体中同时抑制多个ErbB。这些研究应该提供深入了解以前未被重视的作用，ErbB信号网络作为一个关键的调节肢体形态发生。