Ommatidial Patterning during Eye Development

眼睛发育过程中的小眼模式

• 批准号: 7760887
• 负责人: Marek Mlodzik
• 金额: $ 40.73万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760887
• 关键词: Adult; Apoptosis; Area; Biochemical; Biological Assay; Biology; Brain; Cell Culture Techniques; Cell Death; Cell Polarity; Cells; Cytoplasmic Tail; Disease; Drosophila eye; Drosophila genus; Dsh protein; Elements; Event; Eye; Eye Development; Eye diseases; Family; Frizzled Domain; Generations; Goals; Growth Factor; Human; Image; Ligands; Link; Malignant Neoplasms; Mediating; Medical; Membrane; Modeling; Modification; Molecular; Neurons; Norrie' s disease; Notch Signaling Pathway; Nuclear; Outcome; Pathway interactions; Pattern; Phenotype; Phosphorylation; Photoreceptors; Positioning Attribute; Process; Proteins; Proto-Oncogenes; Recruitment Activity; Regulation; Retina; Retinal; Role; Signal Pathway; Signal Transduction; Specificity; Stereotyping; Testing; Vision; Visual system structure; cell fate specification; eye primordia; fly; human FZD3 protein; in vivo; notch protein; receptor; research study; response; retinotopic; stem cell biology; transcription factor

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. The Drosophila eye serves as paradigm for many aspects of eye development, retinal biology and disease. The Drosophila retina is composed of a stereo-typed array of about 800 ommatidia, or unit eyes, each containing a precise arrangement of 8 photoreceptor neurons. The establishment of this precise arrangement requires the interplay of several signaling pathways and transcription factors, all of which are conserved and largely share equivalent functions in the mammalian eye. The correct specification of two of the photoreceptors, R3 and R4, requires an interplay of the Wnt/Frizzled (Fz)/planar cell polarity (PCP) and Notch signaling pathways. Strikingly, the second Fz mediated pathway, canonical (3-Catenin (Cat) signaling, causes photoreceptor cell death and reduction of eye size. As the Fz receptor and (at least) one effector (Dsh) are shared between Fz/|3-Cat and Fz/PCP signaling activating distinct effectors downstream of Dsh, correct ¿regulation of signaling specificity is very critical for normal eye development. The regulation of this signaling ^specificity is only poorly understood. To scope of this application is to define the sequence elements with the ijFz receptor that mediate the specific signaling outcome, and to define the respective modifications on the Dsh ^protein that distinguish between the Fz/|3-Cat and Fz/PCP pathways. Similarly, we will determine the cross- regulatory interactions between Fz/PCP and Notch signaling. A combination of cell culture and biochemical experiments and in vivo studies in the eye will be utilized to achieve these goals. In the human eye, Fz signaling is associated with diseases like Familial Exudative Vitreoretinopathy (FEVR) and the Norrie Disease. Several components of the 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 specification and eye diseases, and will also be of medical relevance in other areas, including stem cell biology.

视觉系统的功能是在大脑中形成图像。正确的规范和图案 视网膜内的光感受器神经元是精确视网膜轴突投影和图像的先决条件 形成。果蝇眼是眼睛发育，视网膜生物学和 疾病。果蝇视网膜由大约800个Ommatidia或单位眼睛的立体型阵列组成 包含8个光感受器神经元的精确排列。建立这种精确安排 需要几种信号通路和转录因子的相互作用，所有这些信号通路和转录因子都保守，并且 在哺乳动物的眼中，很大程度上具有等效功能。两个的正确规范 光感受器R3和R4需要Wnt/毛躁（FZ）/平面细胞极性（PCP）和 Notch信号通路。令人惊讶的是，第二FZ介导的途径，规范（3-catenin（CAT）信号， 引起感光细胞死亡并减少眼睛大小。作为FZ受体和（至少）一个效应器（DSH） 在FZ/| 3-CAT和FZ/PCP信号之间共享，激活DSH下游的不同效果，正确 »信号传导特异性的调节对于正常的眼睛发育至关重要。该信号的调节 ^特异性仅是对特殊性的理解。范围范围是用 介导特定信号结果并定义DSH的相对修饰的IJFZ受体 ^区分FZ/| 3-CAT和FZ/PCP途径的蛋白质。同样，我们将确定交叉 FZ/PCP和Notch信号传导之间的调节相互作用。细胞培养和生化的结合 将利用眼睛中的实验和体内研究来实现这些目标。在人眼中，fz信号传导 与诸如家族性渗出性玻璃体病（FEVR）和Norrie病等疾病有关。一些 FZ和Notch途径的组成部分也与癌症密切相关，并且与干细胞有关 生物学。在本应用程序中获取的信息将提高我们对感光器的理解 规格和眼部疾病，在其他领域（包括干细胞生物学）也将具有医学相关性。