Abstract:
Hedgehog (Hh) proteins constitute one family of a small number of secreted signaling proteins that together regulate multiple aspects of animal development, tissue homeostasis and regeneration. Originally uncovered through genetic analyses in Drosophila, their subsequent discovery in vertebrates has provided a paradigm for the role of morphogens in positional specification. Most strikingly, the Sonic hedgehog protein was shown to mediate the activity of two classic embryonic organizing centers in vertebrates and subsequent studies have implicated it and its paralogs in a myriad of processes. Moreover, dysfunction of the signaling pathway has been shown to underlie numerous human congenital abnormalities and diseases, especially certain types of cancer. This review focusses on the genetic studies that uncovered the key components of the Hh signaling system and the subsequent, biochemical, cell and structural biology analyses of their functions. These studies have revealed several novel processes and principles, shedding new light on the cellular and molecular mechanisms underlying cell-cell communication. Notable amongst these are the involvement of cholesterol both in modifying the Hh proteins and in activating its transduction pathway, the role of cytonemes, filipodia-like extensions, in conveying Hh signals between cells; and the central importance of the Primary Cilium as a cellular compartment within which the components of the signaling pathway are sequestered and interact.
摘要:
Hedgehog(Hh)蛋白构成了一个家族的少量分泌信号蛋白,共同调节动物发育的多个方面,组织稳态和再生。最初是通过果蝇的遗传分析发现的,它们随后在脊椎动物中的发现为形态发生素在位置规范中的作用提供了范例。最引人注目的是,Sonichedgehog蛋白被证明可以介导脊椎动物中两个经典胚胎组织中心的活性,随后的研究将其及其旁系同源物与许多过程有关。此外,信号通路的功能障碍已被证明是许多人类先天性异常和疾病的基础,尤其是某些类型的癌症。这篇综述集中在遗传研究,揭示了Hh信号系统的关键组成部分,生物化学,细胞和结构生物学分析其功能。这些研究揭示了几个新颖的过程和原理,揭示细胞间通讯的细胞和分子机制的新光。其中值得注意的是胆固醇参与修饰Hh蛋白和激活其转导途径,环孢素的作用,filipodia-like扩展名,在细胞之间传递Hh信号;以及初级纤毛作为细胞区室的中心重要性,在该细胞区室中信号通路的组分被隔离并相互作用。