Pigment granule biogenesis in drosophila

在发育过程中，细胞变得专门化，以执行独特的功能。细胞做到这一点的一种方式是形成膜结合的细胞器，存储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小泡。膜细胞器的形成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不同的形态特征，由不同的膜运输途径产生。我们对膜和蛋白质转运机制的大部分了解都来自于对单细胞生物体或培养细胞的研究。因此，人们对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来研究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，磷脂酰肌醇(PI)磷酸盐，在对动物发育至关重要的膜转运途径中的作用。利用这个系统，我们发现了PI 4-磷酸(PI4P)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(PI4KII)或PI 4-磷酸酶SAC1的突变会导致眼睛颜色缺陷，这可以归因于LRO形成的缺陷，我们进一步证明SAC1也是哺乳动物细胞中LRO形成所必需的。因此，通过研究PI4P如何在特征良好的果蝇系统中促进LRO的生物发生，我们的研究将为了解正常人类发育和疾病中涉及的保守的膜运输途径提供洞察力。

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.