Analysis of cis-acting RNA sequences required for intracellular localisation of gurken,the Drosophila TGF alpha homologu

人类、苍蝇和其他多细胞动物由许多特殊的细胞类型组成，它们位于身体的正确位置。如此复杂的结构是如何从第一个简单细胞（受精卵）起源的，这一直是生物学中的一个核心问题。在果蝇中，当信使RNA （mRNA）分子编码信息以制造蛋白质，定位于卵母细胞内的特定位置，从而将蛋白质靶向到细胞的相同部分时，第一个不对称就出现了。这些mrna是如何在它们的分布中受到限制的，人们知之甚少。我们将研究一个关键的mRNA， gurken （grk）如何定位于卵子和胚胎的背侧（后）一半，使其与腹侧（前）一半不同。缺少grk基因的果蝇产下的卵缺少背部结构。我们将使用我们开发的令人兴奋的新方法，使grk mRNA分子发出红光，以便在注射到活的苍蝇卵母细胞和胚胎（0.5mm长）后跟踪其定位。我们将使用发出绿光的蛋白质对卵母细胞和胚胎细胞进行成像，并在mRNA中定义将其定向到其背部目的地的信号。我们还将研究哪些其他基因负责定位以及它们如何实现其功能。Grk与人转化生长因子α (TGFa)有关，TGFa在人卵母细胞成熟过程中起重要作用。TGFa在许多不同的人类癌症和发育性疾病中发生突变。在我们希望治愈这些疾病之前，我们必须首先了解这些分子是如何工作的，但是研究TGFa在人类中的功能受到伦理和技术困难的阻碍。我们对果蝇的这些过程了解得更多，它们的许多基本发育过程被证明与人类惊人地相似。因此，我们预计我们的工作将适用于人类，并可能在长期内更好地了解如何治疗与TGFa功能障碍相关的疾病。

Humans, flies and other multicellular animals, consist of many specialised cell types, located at their correct positions in the body. How such complex structures originate from the first simple cell, which is the fertilised oocyte or egg, has been a central question in biology. In the fruitfly, Drosophila, the first asymmetries arise when messenger RNA (mRNA) molecules that encode the information to make proteins, localise in specific places within the oocyte, and therefore target proteins to the same parts of the cell. How such mRNAs become restricted in their distribution is poorly understood. We will study how one key mRNA, gurken (grk) becomes localised to the dorsal (back) half of the egg and embryo, making it different from the ventral (front) half. Flies missing the grk gene lay eggs missing dorsal structures.We will use exciting new methods we have developed to make grk mRNA molecules emit red light in order to follow their localisation after injection into living fly oocytes and embryos (0.5mm long). We will image the cells of the oocyte and embryos using proteins that emit green light and define the signals in the mRNA that target it to its dorsal destination. We will also investigate what other genes are responsible for the localisation and how they achieve their function. Grk is related to the human transforming growth factor alpha (TGFa), which plays an important role in human oocyte maturation. TGFa is mutated in a number of different human cancers and developmental diseases. Before we can hope to cure such diseases, we must first understand how these molecules work, but studying the function of TGFa in humans is hampered by ethical and technical difficulties. Much more is known about these processes in Drosophila, in which many of the basic processes of development have turned out to be surprisingly similar to humans. We therefore anticipate that our work will be applicable to humans and may lead in the long term to a better understanding of how to cure diseases associated with malfunction of TGFa.