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）：人们对编程产生胰岛素的胰腺β细胞用于治疗I型糖尿病有着浓厚的兴趣，但产生胰岛素的细胞（IPC）规范的机制尚未完全了解。在线虫、苍蝇、小鼠和人类中，胚胎发育过程中产生胰岛素的神经内分泌细胞数量相对较少。然而，无脊椎动物模型系统尚未用于研究 IPC 规范。我们的目标是阐明果蝇中胰岛素生成细胞命运规范的分子和遗传基础。在对果蝇 IPC 功能进行研究之后（Rulifson 等，2002），我们开始研究它们的发育。在 IPC 谱系表达的试点遗传筛选中，我们鉴定了正在发育的 IPC 谱系中的几种基因增强子活性，包括：eyeless/Pax-6、dachshund、optix/Six3 和 Tiptop（与茶衫相关）。这组候选 IPC 发育基因包含用于果蝇和小鼠眼睛规范的保守转录因子网络的组件或密切相关的同源物。使用eyeless、dachshund和tiptop作为分子标记，我们在胚胎发生晚期鉴定了一个假定的IPC祖细胞。根据我们的初步观察，我们假设 IPC 祖细胞是神经母细胞 (NB)，并且所有 IPC 均由该 NB 谱系产生。我们还发现了 PC 结构和功能中对无眼基因功能的需求，这表明我们在 IPC 谱系中确定的其他“眼睛规范”基因具有协同作用。我们假设最早的 IPC 谱系前体中表达的基因将在 IPC 的规范中发挥关键作用。因此，我们有具体的目标：1）识别IPC祖先并确定其起源； 2）检验“眼睛规格”基因对于IPC的发育至关重要的假设； 3) 找到 IPC 谱系规范所必需的其他基因。据我们所知，这将提供第一个 IPC 发育机制的无脊椎动物遗传模型，其中的重要元素将适用于小鼠和人类系统中的 β 细胞编程。