Protein /Nucleic Acid Interactions In Embryogenesis

胚胎发生中的蛋白质/核酸相互作用

• 批准号: 6992792
• 负责人: THOMAS D sargent
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 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/6992792
• 关键词: Xenopus; bone morphogenetic proteins; developmental genetics; ectoderm; embryogenesis; genetic regulation; intermolecular interaction; microarray technology; neural crest; skin; transcription factor; vertebrate embryology

In vertebrates, the ectoderm is subdivided during gastrulation into four primary fates: epidermis and central nervous system (CNS) on the ventral and dorsal surfaces, respectively, and neural crest and sensory placodes located between these two domains. The goal of this project is to understand the mechanisms that determine how ectodermal cells choose between these pathways, and how the ensuing tissue patterning and differentiation are regulated. The experimental approach taken by this laboratory has been to use dependence upon cell-cell signaling as a criterion for identifying genes that may regulate the ectodermal developmental programs. Attention has been focused on the transcriptional activator AP-2alpha. Neural crest induction in Xenopus requires two signals, a partially attenuated BMP signal and a Wnt/beta catenin signal. We have found that AP2alpha is responsible for conveying the BMP signal to the genome, and activation of a broad spectrum of neural crest-specific genes. AP2alpha is also critical in the development of epidermis. We used a hormone-inducible version of AP2alpha as a tool in conjunction with microarray analysis to identifiy target genes in both epidermis and neural crest. Approximately 100 such genes have now been identified, many of which have known functions such as transcription factors, signaling molecules, extracellular matrix-related enzymes and other structural or enzymatic functions. Many also have no known function, but are conserved in the mouse and human genomes and are thus likely to be important. We are now focusing our research on determining the function of a small number of these genes. In particular, we are interested in two; one is a gene we named "Inca" (for Induced in Neural Crest by AP2). Inca is conserved in sequence and expression pattern in frogs, mice, and zebrafish. In the frog, Inca is required for proper development of the craniofacial cartilage and bones, the intestines, and other tissues where neural crest is involved. Another gene encodes an adhesion molecule that is transiently expressed in neural crest and developing somites. In addition we are continuing to study the AP2 family of transcription factors and their role in ectodermal development. Since these genes are conserved throughout vertebrate phylogeny, our findings should have broad relevance to biomedical research and human health and development.

在脊椎动物中，外胚层在原肠胚形成过程中被细分为四个主要命运：分别位于腹侧和背侧表面的表皮和中枢神经系统（CNS），以及位于这两个区域之间的神经嵴和感觉基板。该项目的目标是了解决定外胚层细胞如何在这些途径之间进行选择的机制，以及如何调节随后的组织模式和分化。该实验室采取的实验方法是利用细胞间信号传导的依赖性作为识别可能调节外胚层发育程序的基因的标准。人们的注意力集中在转录激活剂 AP-2alpha 上。非洲爪蟾的神经嵴诱导需要两个信号，部分减弱的 BMP 信号和 Wnt/β 连环蛋白信号。我们发现 AP2alpha 负责将 BMP 信号传递到基因组，并激活广泛的神经嵴特异性基因。 AP2α 在表皮的发育中也至关重要。 我们使用 AP2α 的激素诱导版本作为工具，结合微阵列分析来识别表皮和神经嵴中的靶基因。目前已鉴定出大约 100 个此类基因，其中许多具有已知的功能，例如转录因子、信号分子、细胞外基质相关酶和其他结构或酶功能。许多也没有已知的功能，但在小鼠和人类基因组中是保守的，因此可能很重要。我们现在的研究重点是确定其中少数基因的功能。我们特别对两个感兴趣；其中一个是我们命名为“Inca”的基因（AP2 诱导的神经嵴）。 Inca 在青蛙、小鼠和斑马鱼中的序列和表达模式是保守的。在青蛙中，印加是颅面软骨和骨骼、肠道以及涉及神经嵴的其他组织正常发育所必需的。另一个基因编码在神经嵴和发育体节中瞬时表达的粘附分子。此外，我们正在继续研究 AP2 转录因子家族及其在外胚层发育中的作用。由于这些基因在整个脊椎动物系统发育中都是保守的，因此我们的研究结果应该与生物医学研究以及人类健康和发展具有广泛的相关性。