Cell adhesion and photoreceptor morphogenesis in the retina

描述（申请人提供）：视觉系统的功能是在大脑中形成图像。视网膜内感光神经元的正确规格和模式是精确的视网膜异位轴突投影和图像形成的先决条件。光感受器取向和形态发生的许多方面都是通过调节单个神经元或神经元群的细胞粘附行为而产生的。果蝇的眼睛为眼睛发育、视网膜生物学和疾病的大多数方面提供了范例。果蝇的视网膜是由几百个单位眼或小眼组成的固定阵列，每个小眼包含8个感光神经元的精确排列，这些神经元相互之间以及整个视网膜视野和身体轴都是定向的。这种精确排列的建立需要多种信号通路、转录因子和细胞粘附分子的相互作用。这些都是保守的，在哺乳动物的眼睛中具有相同的功能。不同光感受器亚型的正确定义需要Wnt/卷曲平面细胞极性（Fz-PCP）、Egfr和Notch信号通路的相互作用。遵循细胞命运规范的一个关键方面是称为基质旋转的细胞粘附/细胞运动过程。它导致光感受器前体簇旋转90度，并将它们放置在适当的位置，以允许随后的光感受器形态发生。本应用的范围是剖析信号通路和“执行”细胞粘附因子（以及相关的细胞骨架元件）之间的机制调节相互作用。根据我们的初步研究，我们假设Nemo激酶（MAPK家族成员）整合了Fz/PCP、Notch和受体酪氨酸激酶(RTK)/Ras信号的调节输入，从而调节了几种细胞粘附分子的行为，特别是钙粘蛋白/catenin复合物。引人注目的是，在所有相关的信号通路（Wnt/Fz-PCP， Notch和RTK/Ras）中都采用了一个新的非规范通路分支。这些细胞粘附特异性信号分支的成分现在才被发现，因此一个令人兴奋的新信号网络正在出现。我们将结合果蝇体内研究和生化实验来确定信号成分与细胞粘附因子之间的调节相互作用的机制。在人眼中，Fz和Notch信号与许多疾病有关，如家族性渗出性玻璃体视网膜病变（FEVR）或诺里病（Norrie Disease）。Wnt/Fz和Notch通路的几个组成部分也与癌症密切相关，并与干细胞生物学相关。因此，在此应用程序中获得的信息将促进我们对光感受器形态发生和眼病的理解，并且也将在其他领域具有医学相关性，包括干细胞生物学和癌症。公共卫生相关性：RTK/Ras， Notch和Wnt/ fz平面细胞极性信号通路与许多生长和模式环境有关，并与许多疾病有关，从视网膜变性和血管生成缺陷到癌症。该应用程序解决了这些通路的调节输入，这些通路在感光神经元和上皮细胞的模式中是特异性的细胞粘附、运动和形态发生。在这里获得的信息将对几种眼病和其他医学疾病具有重要意义。

DESCRIPTION (provided by applicant): The function of the visual system is to form images in the brain. Correct specification and patterning of the photoreceptor neurons within the retina are a prerequisite for precise retinotopic axonal projections and image formation. Many aspects of photoreceptor orientation and morphogenesis are generated through regulated cell adhesion behavior of individual neurons or groups of neurons. The Drosophila eye serves as a paradigm for most aspects of eye development, retinal biology and disease. The Drosophila retina is composed of a stereo-typed array of several hundred unit eyes, or ommatidia, each containing a precise arrangement of 8 photoreceptor neurons, which are oriented with respect to each other and also the whole retinal field and body axes. The establishment of this precise arrangement requires the interplay of several signaling pathways, transcription factors, and cell adhesion molecules. These are conserved and share equivalent functions in the mammalian eye. The correct specification of different photoreceptor subtypes requires an interplay of the Wnt/Frizzled-planar cell polarity (Fz-PCP), Egfr and Notch signaling pathways. A critical aspect that follows the cell fate specification is a cell adhesion/cell motility process called ommatidial rotation. It leads to a 90 degree rotation of clusters of photoreceptor precursors and places them in their proper position to allow subsequent photoreceptor morphogenesis. The scope of this application is to dissect the mechanistic regulatory interactions between the signaling pathways and the "executing" cell adhesion factors (and associated cytoskeletal elements). Based on our preliminary studies we hypothesize that the Nemo kinase (a MAPK family member) integrates regulatory input from Fz/PCP, Notch and receptor tyrosine kinase (RTK)/Ras signaling to itself regulate the behavior of several cell adhesion molecules and in particular the cadherin/catenin complexes. Strikingly, in all involved signaling pathways (Wnt/Fz-PCP, Notch and RTK/Ras) a novel non-canonical pathway branch is employed. The components of these cell adhesion specific signaling branches are only being discovered now, and thus an exciting new signaling network is emerging. We will use a combination of Drosophila in vivo studies and biochemical experiments to define the mechanistic regulatory interactions between the signaling components and the cell adhesion factors. In the human eye, Fz and Notch signaling are associated with many diseases, like Familial Exudative Vitreoretinopathy (FEVR) or Norrie Disease. Several components of the Wnt/Fz and Notch pathways are also critically linked to cancer and are associated with stem cell biology. Thus the information acquired in this application will advance our understanding of photoreceptor morphogenesis and eye diseases, and will also be of medical relevance in other areas, including stem cell biology and cancer. PUBLIC HEALTH RELEVANCE: RTK/Ras, Notch and Wnt/Fz-planar cell polarity signaling pathways have been implicated in many growth and patterning contexts, and are linked to many diseases, ranging from retinal degeneration and angiogenesis defects to cancer. This application addresses the regulatory input of these pathways that is specific to cell adhesion, motility and morphogenesis in the patterning of photoreceptor neurons and epithelial cells in general. The information acquired here will be of importance for several eye diseases and other medical disorders.