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，由许多特殊类型的细胞组成，它们位于身体的正确位置。这种复杂的结构如何起源于第一个简单的细胞，即受精的卵母细胞或卵子，一直是生物学的中心问题。在果蝇中，当编码制造蛋白质的信息的信使RNA(MRNA)分子定位在卵母细胞内的特定位置，从而将蛋白质靶向细胞的相同部分时，第一个不对称就会出现。这些mRNAs是如何在分布上受到限制的，目前还知之甚少。我们将研究一种关键的mRNA Gurken(GRK)如何定位于卵和胚胎的背(后)半部分，使其不同于腹侧(前)半部分。缺少grk基因的苍蝇产卵时缺少背部结构。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(0.5 mm长)后跟踪它们的定位。我们将使用发出绿色光的蛋白质对卵母细胞和胚胎的细胞进行成像，并定义mRNA中的信号，将其定向到其背部目的地。我们还将调查哪些其他基因负责本地化，以及它们是如何实现其功能的。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。在我们有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，但研究TGFa在人类中的功能受到伦理和技术困难的阻碍。人们对果蝇的这些过程有更多的了解，在这些过程中，许多基本的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，从长远来看，可能会导致更好地理解如何治疗与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.