Role of a Novel EGF-Related Growth Factor in Mouse Gastrulation

新型 EGF 相关生长因子在小鼠原肠胚形成中的作用

• 批准号: 9630903
• 负责人: Michael Shen
• 金额: $ 30万
• 依托单位: Rutgers, The State University of New Jersey-RBHS-Robert Wood
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9630903&HistoricalAwards=false
• 关键词: Role; Novel; EGF; Related; Growth

9630903 Shen To understand the molecular mechanisms that regulate embryonic pattern formation and differentiation, it is necessary to identify candidate growth factors that may be involved in these processes, and to characterize their functional properties. Previous studies of mouse embryogenesis in this laboratory have used a differential display screening approach to identify mesoderm-specific genes expressed during the differentiation of embryonic stem (ES) cells in culture. This strategy has resulted in the isolation of a novel gene named Cryptic, which encodes a potentially secreted molecule containing a single copy of an epidermal growth factor-like (EGF) motif. Analysis of Cryptic expression indicates that it is expressed during gastrulation in two distinct spatial domains, which correspond to the axial mesoderm and to the lateral plate mesoderm. Thus, the novel gene Cryptic encodes a potential signaling molecule that has an expression pattern consistent with a role in mesoderm patterning and differentiation. Notably, Cryptic appears to be a member of a new family of EGF-related growth factors. The Cryptic gene was originally named on the basis of its significant sequence similarities with the Cripto gene, which is also expressed during mesoderm formation and has growth stimulating activities in cell culture. The Cryptic gene is also related to a recently described Xenopus gene named FRL-1, which has mesoderm - and neural-inducing activities in embryonic assays, and can activate fibroblast growth factor IFGF) receptors. Based on (1) the sequence similarities between Cryptic, Cripto, and FRL-1, (2) the growth factor activity of Cripto, (3) the mesoderm and neural-inducing activities of FRL-1, (4) the activation of FGF receptors by FRL-1, and (5) the spatially and temporally restricted pattern of Cryptic expression, it is likely that Cryptic encodes a potential signaling molecule that may be involved in cellular interactions during embryonic pattern formation and cell fate det ermination. To address this hypothesis, the proposed research will investigate the biological and biochemical properties of Cryptic, organized around three specific aims: (1) Characterization of Cryptic mRNA and protein expression patterns, (2) Investigation of the biochemical properties and function of CRYPTIC protein and its receptor, and (3) Analysis of biological requirements for Cryptic during mouse development. Taken together, these studies will synergize to provide a greater understanding of the biological and biochemical functions of this novel growth factor-like molecule, and perhaps those related family members. Furthermore, these investigations may lead to insights concerning the molecular mechanisms involved in growth factor signaling during embryonic patterning and differentiation in vertebrate development.

9630903 Shen 为了了解调节胚胎模式形成和分化的分子机制，有必要识别可能参与这些过程的候选生长因子，并表征其功能特性。 该实验室之前对小鼠胚胎发生的研究使用了差异显示筛选方法来鉴定培养中胚胎干（ES）细胞分化过程中表达的中胚层特异性基因。 这一策略导致分离出一种名为 Cryptic 的新基因，该基因编码一种潜在的分泌分子，其中含有表皮生长因子样 (EGF) 基序的单个拷贝。 对隐性表达的分析表明，它在原肠胚形成期间在两个不同的空间域中表达，这两个空间域对应于轴向中胚层和侧板中胚层。 因此，新基因 Cryptic 编码一种潜在的信号分子，其表达模式与中胚层模式和分化中的作用一致。 值得注意的是，Cryptic 似乎是 EGF 相关生长因子新家族的成员。 Cryptic 基因最初因其与 Cripto 基因显着的序列相似性而命名，Cripto 基因也在中胚层形成过程中表达，并在细胞培养物中具有生长刺激活性。 Cryptic 基因还与最近描述的名为 FRL-1 的爪蟾基因相关，该基因在胚胎测定中具有中胚层和神经诱导活性，并且可以激活成纤维细胞生长因子（IFGF）受体。 基于 (1) Cryptic、Cripto 和 FRL-1 之间的序列相似性，(2) Cripto 的生长因子活性，(3) FRL-1 的中胚层和神经诱导活性，(4) FGF 的激活FRL-1受体，以及（5）Cryptic表达的空间和时间限制模式，Cryptic很可能编码一种潜在的信号分子，该分子可能参与胚胎模式形成过程中的细胞相互作用和细胞命运的决定。 为了解决这一假设，拟议的研究将围绕三个具体目标来调查 Cryptic 的生物和生化特性：(1) Cryptic mRNA 和蛋白质表达模式的表征，(2) 研究 CRYPTIC 蛋白质和蛋白质的生化特性和功能。 (3) 小鼠发育过程中 Cryptic 的生物学需求分析。 总而言之，这些研究将协同作用，以更好地了解这种新型生长因子样分子以及可能相关的家族成员的生物学和生化功能。 此外，这些研究可能有助于深入了解脊椎动物发育过程中胚胎模式和分化过程中生长因子信号传导所涉及的分子机制。