Pigment granule biogenesis in drosophila

果蝇色素颗粒的生物发生

• 批准号: 262166-2010
• 负责人: Brill, Julie
• 金额: $ 1.97万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=505771
• 关键词: Pigment; granule; biogenesis; drosophila

During development, cells become specialized to carry out unique functions. One way cells do this is to form membrane-bound organelles that store factors required by that particular cell type. For example, hormone- secreting cells form secretory granules that contain hormones, and nerves form synaptic vesicles that contain neurotransmitters. Defects in formation of membrane organelles typically lead to severe human diseases, many of which are fatal. Different classes of organelles have characteristic morphologies and are produced by distinct membrane trafficking pathways. Much of what we know about mechanisms of membrane and protein transport comes from studies in single cell organisms or cultured cells. Hence, remarkably little is known about how organelles form in developing tissues of a multicellular organism. We use the fruit fly Drosophila melanogaster as a powerful model in which to investigate molecular mechanisms involved in organelle biogenesis. In particular, we have been studying the roles of an important class of membrane lipids, the phosphatidylinositol (PI) phosphates, in membrane trafficking pathways that are important for animal development. Using this system, we uncovered a novel role for PI 4-phosphate (PI4P) and its regulatory enzymes in the formation of pigment granules, which are lysosome-related organelles (LROs) required for normal eye color. We discovered that mutations in the type II PI 4-kinase (PI4KII) or in the PI 4-phosphatase Sac1 cause eye color defects that can be attributed to defects in LRO formation, and we further showed that Sac1 is also required for formation of LROs called melanosomes in mammalian cells. Thus, by studying how PI4P contributes to LRO biogenesis in the well-characterized Drosophila system, our research will provide insight into conserved membrane trafficking pathways involved in normal human development and disease.

在发育过程中，细胞变得专门化以执行独特的功能。细胞这样做的一种方式是形成膜结合的细胞器，储存特定细胞类型所需的因子。例如，激素分泌细胞形成含有激素的分泌颗粒，神经形成含有神经递质的突触囊泡。膜细胞器形成的缺陷通常会导致严重的人类疾病，其中许多是致命的。不同种类的细胞器具有特征性的形态，并通过不同的膜运输途径产生。我们对膜和蛋白质转运机制的了解大部分来自对单细胞生物或培养细胞的研究。因此，对于多细胞生物体的发育组织中细胞器是如何形成的知之甚少。我们使用果蝇作为一个强大的模型，在其中调查参与细胞器生物发生的分子机制。特别是，我们一直在研究一类重要的膜脂质，磷脂酰肌醇（PI）磷酸盐，在膜运输途径，是重要的动物发育的作用。使用这个系统，我们发现了PI 4-磷酸（PI 4P）及其调节酶在色素颗粒形成中的新作用，色素颗粒是正常眼睛颜色所需的溶酶体相关细胞器（LRO）。我们发现II型PI 4-激酶（PI 4KII）或PI 4-磷酸酶Sac 1的突变导致眼睛颜色缺陷，这可归因于LRO形成缺陷，我们进一步表明Sac 1也是哺乳动物细胞中称为黑素体的LRO形成所必需的。因此，通过研究PI 4P如何有助于LRO生物合成的特点果蝇系统，我们的研究将提供深入了解保守的膜运输途径参与正常的人类发育和疾病。