MOLECULAR MECHANISMS OF HEDGEHOG SIGNALING

这项研究的长期目标是了解 在发育和成人中控制细胞间信号传导的机制 组织中 Hedgehog（Hh）信号蛋白控制细胞命运， 通过调节特定基因在动物发育过程中增殖 表情 在脊椎动物中，Hh蛋白质在不同的组织中形成模式， 发育中的四肢脊柱和大脑 膜蛋白 Patched（Ptc）对抗Hh到Hd特异性基因表达。 在 果蝇，ptc突变导致Hh靶基因的错误表达， 导致异常发育和细胞增殖。中的突变 ptc的人类同源物PTCH 1导致非常常见的皮肤肿瘤，基底 细胞癌和脑肿瘤髓母细胞瘤。 PTCH1也是 在基底细胞痣综合征中发生了突变， 以许多发育缺陷和肿瘤为特征。 分子 Hh信号接收和转导的机制在很大程度上是未知的。 理解Hh信号传导在发育中的作用的核心， 疾病是学习如何Ptc的功能和识别蛋白质与 它们相互作用。 Ptc被认为结合Hh蛋白， 与Smoothened（Smo）（一种膜蛋白）相关并调节Smoothened（Smo），一种膜蛋白 需要Hh信号。 Ptc还隔离Hh以限制其范围 的行动。 Ptc如何以及在何处介导这些重要的调控 过程是未知的。 Ptc可能在囊泡运动中起作用， 这是因为它与NPC1（一种膜蛋白）的序列相似性 与胆固醇的细胞内运输有关。 的 拟议的研究将确定Ptc的关键功能域 并表征Ptc的细胞定位及其相互作用 配体结合后的蛋白质。 利用果蝇， Hh信号传导将通过涉及特定的 PTC表型

The long term objective of this research is to understand the molecular mechanisms that control cell-cell signaling in developing and adult tissues. Hedgehog (Hh) signaling proteins control cell fates and proliferation during animal development by regulating the specific gene expression. In vertebrates, Hh proteins pattern diverse tissues such as the developing limb, spinal column, and brain. The membrane protein Patched (Ptc) opposes Hh to inactivate specific gene expression. In Drosophila, ptc mutations cause misexpression of Hh target genes and result in abnormal development and cell proliferation. Mutations in a human homolog of ptc, PTCH1 lead to the very common skin tumor, basal cell carcinoma, and to the brain tumor, medulloblastoma. PTCH1 is also mutated in the basal cell nevus syndrome, an inherited disorder characterized by many developmental defects and tumors. The molecular mechanisms of Hh signal reception and transduction are largely unknown. Central to understanding the role of Hh signaling in development and disease is learning how Ptc functions and identifying proteins with which it interacts. Ptc is proposed to bind Hh proteins and to associate with and regulate, Smoothened, (Smo), a membrane protein required for Hh signaling. Ptc also sequesters Hh to limit its range of action. How and where Ptc mediates these important regulatory processes is not known. Ptc may function in vesicle movement as suggested by its sequence similarity to NPC1, a membrane protein implicated in the intracellular trafficking of cholesterol. The proposed studies will identify the critical functional domains of Ptc and characterize the cellular localization of Ptc and its interacting proteins following ligand binding. Using Drosophila, new components of Hh signaling will be identified by a genetic screen involving a specific ptc phenotype.