TISSUE SPECIFICITY OF WINGLESS SIGNALING IN DROSOPHILA

相邻细胞之间的信号对发育过程中许多细胞命运的决定至关重要。令人惊讶的是，相同的分泌信号经常在不同的组织中使用，以引发明显无关的细胞反应。我们的目标是通过一个相对简单的由果蝇分泌蛋白Wingless(Wg)进行组织特异性调控的例子，更好地理解这种现象背后的分子机制。在发育中的苍蝇翅膀中，Wg是形成感觉刚毛所必需的。然而，在眼睛里，Wg信号阻止细胞采用刷毛细胞的命运。这两个组织中的刚毛前体细胞都接受Wg信号，但它们对信号的解释不同。为了更多地了解WG信号的组织特异性方面，提出了两种方法。我们已经确定无女儿(Da)基因是眼睛中依赖于Wg的刷毛抑制的潜在直接靶点。我们将确定这种调节的分子机制，以及Da是否是Wg信号在翅膀中的靶标。第二种方法是鉴定两个基因，它们的突变表型表明它们在组织特异性Wg信号中发挥重要作用。其中一个基因编码一种蛋白激酶，这是Wg调节眼睛中的刚毛形成所必需的，但在翅膀中不是。基因突变分析以及对该激酶的生化特征将确定其与Wg信号通路的已知成分之间的关系。第二个基因在眼睛中扮演Wg信号的积极效应者的角色，但它对抗翅膀中的信号通路。该基因将被克隆和测序，以阐明其在Wg信号中所起的作用。我们预计，这两种方法将会聚在一个模型上，以解释Wg对刷毛形成的组织特异性控制。WG是广泛存在于动物界的分泌蛋白大家族(Wnts)中最具特征的成员之一。WNTs在无脊椎动物和脊椎动物的发育过程中都发挥着重要的作用。此外，Wnt信号与小鼠和人类的肿瘤发生有关。由于Wnt信号转导机制在进化上也是保守的，了解果蝇Wg信号的组织特异性机制应该与其他生物具有广泛的相关性。

Signaling between neighboring cells is crucial for many cell fate decisions during development. Surprisingly, the same secreted signals are often used in different tissues to elicit apparently unrelated cellular responses. Our goal is to understand better the molecular mechanisms underlying this phenomenon, using a relatively simple example of tissue-specific regulation by the Drosophila secreted protein Wingless (Wg). In the developing fly wing, Wg is required for the formation of sensory bristles. However, in the eye Wg signaling prevents cells from adopting a bristle cell fate. The bristle precursor cells in both tissues receive the Wg signal, but they interpret the signal differently. To learn more about the tissue-specific aspects of Wg signaling, two approachers are proposed. We have identified the daughterless (da) gene as potential direct target of Wg-dependent bristle inhibition in the eye. We will determine the molecular mechanism of this regulation and whether Da is a target of Wg signaling in the wing. The second approach is to characterize two genes whose mutant phenotypes indicate that they play important roles in tissue-specific Wg signaling. One gene encodes a protein kinase that is required for Wg regulation of bristle formation in the eye but not in the wing. Genetic epitasis analysis as well as biochemical characterization of the kinase will determine its relationship to known components of the Wg signaling pathway. The second gene acts as a positive effector of Wg signaling in the eye, but it antagonizes the pathway in the wing. This gene will be cloned and sequenced to elucidate the role it plays in Wg signaling. We expect that the two approaches will converge on a model to explain the tissue- specific control of bristle formation by Wg. Wg is one of the best characterized members of a large family of secreted proteins (known as Wnts) conserved throughout the animal kingdom. Wnts have been found to play many important roles in the development of both invertebrates and vertebrates. In addition, Wnt signaling has been implicated in tumorigenesis in mice and humans. Since the machinery for Wnt signal transduction is also evolutionarily conserved, understanding tissue specific mechanisms of Wg signaling in flies should have broad relevance to other organisms.