Gradient Morphogens and Body Patterning Mechanisms

梯度形态发生剂和身体图案形成机制

• 批准号: 0744966
• 负责人: Stephen Small
• 金额: --
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0744966&HistoricalAwards=false
• 关键词: Gradient; Morphogens; Body; Patterning; Mechanisms

Stephen J. SmallProposal IOS-0744966Gradient morphogens and body patterning mechanisms In the fruit fly Drosophila melanogaster (Dm), the maternal transcription factor Bicoid (Bcd) is distributed in a long range nuclear gradient along the anterior posterior (AP) axis of the early embryo. Mutations in Bcd function cause the complete loss of the head and other anterior structures, and the formation of tail-like structures at both ends of the embryo. At the molecular level, Bcd is a master regulator that specifies anterior development via two major pathways. First, Bcd prevents the translation of Caudal, a protein involved posterior development. Second, Bcd activates transcription of more than twenty target genes, each of which is responsible for part of the network that makes anterior structures. Despite its importance in Dm, Bcd is not found in most insects. However, recent studies suggest that another transcription factor, Orthodentical (Otd), may play the role of master anterior regulator in at least two other insects, which are distantly related to Dm. This is surprising because there is very little amino acid sequence similarity between the Bcd and Otd proteins. In preliminary experiments, a genetic engineering approach was used to replace the maternal Bcd gradient in Dm with a similar gradient of Otd. Surprisingly, maternally provided Otd rescued most of the anterior structures missing in mutants lacking Dm Bcd. Thus, the goal of this research is to understand why proteins of such different structures can provide similar functions in embryonic development. The experiments will define exactly which specific Bcd-dependent activities can be provided by Otd, and then test which parts of the Bcd and Otd proteins are required for turning on the target genes involved in anterior patterning. The results of these experiments will be of great interest to researchers in the fields of developmental biology, molecular evolution, and computational biology, and will have Broader Impacts from a scientific perspective. In terms of educational Broader Impacts, the project will also provide excellent training opportunities for students at the undergraduate and graduate levels, and augment current efforts to attract and train under-represented minority students.

Stephen J. SmallProposal IOS-0744966梯度形态发生素和身体模式形成机制在果蝇Drosophila melanogaster（Dm）中，母体转录因子Bicoid（Bcd）沿着早期胚胎的前后（AP）轴以长距离核梯度分布。 Bcd功能的突变会导致头部和其他前部结构的完全丧失，并在胚胎的两端形成尾状结构。 在分子水平上，Bcd是通过两个主要途径指定前部发育的主调节器。 首先，Bcd阻止Caudal的翻译，Caudal是一种参与后部发育的蛋白质。 其次，Bcd激活了20多个靶基因的转录，每个靶基因都负责形成前部结构的网络的一部分。 尽管Bcd在Dm中很重要，但它在大多数昆虫中并不存在。 然而，最近的研究表明，另一个转录因子，Orthodentical（Otd），可能发挥的作用，至少有两个其他昆虫，这是远亲Dm的主前调节。 这是令人惊讶的，因为在Bcd和Otd蛋白质之间存在非常小的氨基酸序列相似性。 在初步实验中，使用基因工程方法将Dm中的母体Bcd梯度替换为类似的Otd梯度。 令人惊讶的是，母体提供的Otd挽救了缺乏Dm Bcd的突变体中缺失的大部分前部结构。 因此，这项研究的目的是了解为什么这种不同结构的蛋白质可以在胚胎发育中提供相似的功能。 这些实验将准确定义Otd可以提供哪些特定的Bcd依赖性活动，然后测试Bcd和Otd蛋白的哪些部分是开启参与前部模式的靶基因所必需的。 这些实验的结果将引起发育生物学、分子进化和计算生物学领域研究人员的极大兴趣，并将从科学角度产生更广泛的影响。 就教育的更广泛影响而言，该项目还将为本科生和研究生提供极好的培训机会，并加强目前吸引和培训代表性不足的少数民族学生的努力。