Development of insulin-producing cells in Drosophila

果蝇胰岛素产生细胞的发育

• 批准号: 6995192
• 负责人: ERIC J RULIFSON
• 金额: $ 18.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6995192
• 关键词: Drosophilidae; RNA interference; biological models; biological signal transduction; cell cell interaction; cell differentiation; developmental genetics; ectoderm; gene expression; gene targeting; genetic screening; insulin; model design /development; mutant; nerve stem cell; pancreatic islet function; phenotype

DESCRIPTION (provided by applicant): There is intense interest in the programming of insulin-producing pancreatic beta cells for treatment of Type I diabetes, but the mechanism of insulin-producing cell (IPC) specification is not entirely understood. In worms, flies, mice and humans, relatively small populations of insulin-producing neuroendocrine cells are specified in embryonic development; however, invertebrate model systems have not yet been employed to study IPC specification. Our goal is to elucidate the molecular and genetic basis of insulin-producing cell fate specification in Drosophila. Following a study of Drosophila IPC function (Rulifson et al., 2002), we have begun to examine their development. In a pilot genetic screen for IPC lineage expression, we identified several gene enhancer activities in the developing IPC lineage, including: eyeless/Pax-6, dachshund, optix/Six3, and tiptop (teashirt-related). This set of candidate IPC development genes comprises either components or closely related homologues of a conserved transcription factor network for eye specification in Drosophila and mouse. Using eyeless, dachshund and tiptop as molecular markers, we identified a putative IPC progenitor at late embryogenesis. Based on our preliminary observations, we hypothesize that the IPC progenitor is a neuroblast (NB), and that all IPCs are produced from this one NB lineage. We have also found a requirement for eyeless gene function in [PC structure and function, suggesting a concerted role for the other "eye specification" genes we identified in the IPC lineage. We hypothesize that genes expressed within the earliest IPC lineage precursors will have key roles in specification of IPCs. Thus, we have the specific aims: 1) Identify the IPC progenitor and establish its origin; 2) Test the hypothesis that the "eye specification" genes are essential for development of IPCs; 3) Find additional genes essential for IPC lineage specification. To the best of our knowledge, this will provide the first invertebrate genetic model of IPC developmental mechanisms, significant elements of which will be applicable to beta cell programming in mouse and human systems.

描述（由申请人提供）：对产生胰岛素的胰腺β细胞的编程以治疗I型糖尿病，但产生胰岛素产生细胞（IPC）规范的机制并不完全了解。在蠕虫，小鼠和人类中，在胚胎发育中指定了相对较少的产生胰岛素神经内分泌细胞的种群。但是，尚未使用无脊椎动物模型系统来研究IPC规范。我们的目标是阐明果蝇中产生胰岛素细胞命运规范的分子和遗传基础。经过果蝇IPC功能的研究（Rulifson等，2002），我们开始研究它们的发展。在IPC谱系表达的试验遗传筛选中，我们确定了发育中的IPC谱系中的几种基因增强剂活性，包括：Eyeless/Pax-6，Dachshund，Optix/Six3和Tiptop（与茶有关）。这组候选IPC开发基因包括果蝇和小鼠中的保守转录因子网络的组件或密切相关的同源物。使用无眼，腊肠犬和tiptop作为分子标记，我们在晚期胚胎发生下确定了一个假定的IPC祖细胞。基于我们的初步观察，我们假设IPC祖细胞是神经细胞（NB），并且所有IPC都是从该NB谱系中产生的。我们还发现了[PC结构和功能中的无眼基因功能的要求，这表明我们在IPC谱系中鉴定出的其他“眼睛规格”基因发挥了一致作用。我们假设在最早的IPC谱系前体中表达的基因将在IPC规范中具有关键作用。因此，我们有具体的目的：1）确定IPC祖先并确定其起源； 2）检验“眼睛规范”基因对于开发IPC至关重要的假设； 3）找到IPC谱系规范必不可少的其他基因。据我们所知，这将提供IPC发育机制的第一个无脊椎动物遗传模型，其重要元素将适用于小鼠和人类系统中的β细胞编程。