刺猬信号通路

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信号传导途径示意图,右中为刺蝟因子

刺猬信号通路英语Hedgehog signaling pathway)是重要的信号传导通路。

刺猬信号通路是动物发育的关键调控之一,在所有的两侧对称动物中都有表达。刺猬信号通路得名于在其多肽配体——Drosophila果蝇中发现的一种名为Hh的细胞间信号分子。Hh是 Drosophila体节极性基因的表达物,是果蝇体形发育形成的基础。该分子在后期胚胎开成及变态期及起重要作用。[1]

共有五種刺蝟因子:音蝟因子(Sonic hedgehog,SHH)、沙漠刺蝟因子(desert hedgehog,DHH)、印度刺蝟因子(Indian hedgehog,IHH)、Echidna Hedgehog,EHH和Tiggywinkle Hedgehog,TwHH)。仅在鱼类中发现有EHH和TwHH,哺乳类和其他动物中没有这两种刺蝟因子。

哺乳动物有三种刺猬信号路径同系物,DHH、IHH及SHH,其中Sonic研究得最深入。该路径在脊椎动物胚胎发育中同样的重要。缺乏该路径组件的基因敲除小鼠,其大大脑、骨骼、肌肉系统、胃肠道及肺都未能正正常发育。近期研究表明刺猬信号路径在调节对成人组织起到维护及再生作用的成体干细胞中的作用。同样该路径也与某些癌症的发生的关系。几家制药公司正在积极的开发针通过刺猬信号传导以对抗癌症的药物。

发现[编辑]

File:Denticlebands.png
图1.正常幼虫与刺猬hedgehog突变的幼虫

在20世纪70年代,发育生物学的基本问题是一个相对简单的受精卵是如何发展成一个复杂的身体分节英语Segmentation (biology)的动物的。70年代末,克里斯汀·纽斯林-沃尔哈德艾瑞克·威斯乔斯分离了控制果蝇前后体轴发育分节的突变基因[2],他们的“饱和诱变”技术导致了一系列参与体轴形态发生英语Morphogenesis基因的发现。1995年,他们因在对果蝇胚胎发育英语Drosophila embryogenesis基因突变的研究工作与爱德华·路易斯共同获得诺贝尔奖[3]

果蠅的刺蝟 (hh) 基因被發現為其中一種可以造成個體體節前後差異的重要基因。果蠅的刺蝟基因在1992年分別被 Jym Mohler, Philip Beachy, 以及 Thomas B. Kornberg的實驗室所複製出來。 若其中一些刺蝟基因發生突變,將會造成相較於野生型來說,較為短小且矮胖的不正常形狀胚胎。 The function of the hedgehog segment polarity gene has been studied in terms of its influence on the normally polarized distribution of larval cuticular denticles as well as features on adult appendages such as legs and antennae.[4] Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). The appearance of the stubby and "hairy" larvae inspired the name 'hedgehog'.

果蝇[编辑]

圖 2. Production of the CiR transcriptional repressor when Hh is not bound to Patched. In the diagram, "P" represents phosphate.
圖 3. 當 Hh 和 Patched (PTCH) 結合時, Ci 蛋白便可以在細胞核中扮演轉錄因子的角色。

机制[编辑]

昆蟲細胞表現出大量含有鋅指轉錄因子 Cubitus interruptus (Ci蛋白), 而此蛋白會在細胞質中和 kinesin- like protein Costal-2 (Cos2) 形成複合體並結合到微管上 (圖 2)。 The SCF complex targets the 155 kDa full length Ci protein for proteosome-dependent cleavage, which generates a 75 kDa fragment (CiR). CiR builds up in the cell and diffuses into the nucleus, where it acts as a co-repressor for Hh target genes.[5] The steps leading to Ci protein proteolysis include phosphorylation of Ci protein by several protein kinases; PKA, GSK3β and CK1 (Figure 2).[6] The Drosophila protein Slimb is part of an SCF complex that targets proteins for ubiquitylation. Slimb binds to phosphorylated Ci protein.

In the absence of Hh (圖 3), a cell-surface transmembrane protein called Patched (PTCH) acts to prevent high expression and activity of a 7 membrane spanning receptor[7] called Smoothened (SMO). Patched has sequence similarity to known membrane transport proteins. When extracellular Hh is present (Figure 3), it binds to and inhibits Patched, allowing Smoothened to accumulate and inhibit the proteolytic cleavage of the Ci protein. This process most likely involves the direct interaction of Smoothened and Costal-2 and may involve sequestration of the Ci protein-containing complex to a microdomain where the steps leading to Ci protein proteolysis are disrupted.[5] The mechanism by which Hh binding to Patched leads to increased levels of Smoothened is not clear (Step 1 in Figure 3). Following binding of Hh to Patched, Smoothened levels increase greatly over the level maintained in cells when Patched is not bound to Hh.[8] It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels.[9]

In cells with Hh-activated Patched (Figure 3), the intact Ci protein accumulates in the cell cytoplasm and levels of CiR decrease, allowing transcription of some genes such as decapentaplegic (dpp, a member of the BMP growth factor family). For other Hh-regulated genes, expression requires not only the loss of CiR but also the positive action of uncleaved Ci to act as a transcriptional activator.[6] Costal-2 is normally important for holding Ci protein in the cytoplasm, but interaction of Smoothened with Costal-2 allows some intact Ci protein to go to the nucleus. The Drosophila protein Fused (Fu in Figure 3) is a protein kinase that binds to Costal-2. Fused can inhibit Suppressor of Fused (SUFU), which in turn interacts with Ci to regulate gene transcription in some cell types.[10]

作用[编辑]

Figure 4. Interactions between Wingless and Hedgehog.

Hedgehog has roles in larval body segment development and in formation of adult appendages. During the formation of body segments in the developing Drosophila embryo, stripes of cells that synthesize the transcription factor Engrailed can also express the cell-to-cell signaling protein Hedgehog (green in Figure 4). Hedgehog is not free to move very far from the cells that make it and so it only activates a thin stripe of cells adjacent to the Engrailed-expressing cells. When acting in this local fashion, hedgehog works as a paracrine factor. Only cells to one side of the Engrailed-expressing cells are competent to respond to Hedgehog following interaction of Hh with the receptor protein Patched (blue in Figure 4).

Cells with Hh-activated Patched receptor synthesize the Wingless protein (red in Figure 4). If a Drosophila embryo is altered so as to produce Hh in all cells, all of the competent cells respond and form a broader band of Wingless-expressing cells in each segment. The wingless gene has an upstream transcription regulatory region that binds the Ci transcription factor in a Hh-dependent fashion resulting in an increase in wingless transcription (interaction 2 in Figure 3) in a stripe of cells adjacent to the stripe of Hh-producing cells.[11]

Wingless protein acts as an extracellular signal and patterns the adjacent rows of cells by activating its cell surface receptor Frizzled. Wingless acts on Engrailed-expressing cells to stabilize the stripes of Engrailed expression. Wingless is a member of the Wnt family of cell-to-cell signaling proteins. The reciprocal signaling by Hedgehog and Wingless stabilizes the boundary between parasegments (Figure 4, top). The effects of Wingless and Hedgehog on other stripes of cells in each segment establishes a positional code that accounts for the distinct anatomical features along the anterior-posterior axis of the segments [12]

The Wingless protein is called "wingless" because of the phenotype of some wingless fly mutants. Wingless and Hedgehog functioned together during metamorphosis to coordinate wing formation. Hedgehog is expressed in the posterior part of developing Drosophila limbs. Hedgehog also participates in the coordination of eye, brain, gonad, gut and tracheal development. Hedgehog has been implicated in reduced eye development in the amphipod Gammarus minus. Specifically, downregulation of hedgehog results in reduced eyes.[13]

環節動物[编辑]

脊椎动物[编辑]

机制[编辑]

作用[编辑]

人类疾病[编辑]

胚胎发育时缺少刺蝟因子(因基因突变或孕妇误食致畸剂)都会导致严重的发育异常。

进化[编辑]

研究[编辑]

参考文献[编辑]

  1. ^ Ingham, Philip W.; Nakano, Yoshiro; Seger, Claudia. Mechanisms and functions of Hedgehog signalling across the metazoa. Nature Reviews Genetics. 2011, 12 (6): 393–406. doi:10.1038/nrg2984. PMID 21502959. 
  2. ^ Nüsslein-Volhard, Christiane; Wieschaus, Eric. Mutations affecting segment number and polarity in Drosophila. Nature. 1980, 287 (5785): 795–801. doi:10.1038/287795a0. PMID 6776413. 
  3. ^ 1995 Nobel Prize for discovery of the genetic control of early embryonic development
  4. ^ Mohler, Jym. Requirements for hedgehog, a Segmental Polarity Gene, in Patterning Larval and Adult Cuticle of Drosophila. Genetics. December 1988, 120 (4): 1061–72. PMC 1203569. PMID 3147217. 
  5. ^ 5.0 5.1 Collins, R. T.; Cohen, SM. A Genetic Screen in Drosophila for Identifying Novel Components of the Hedgehog Signaling Pathway. Genetics. 2005, 170 (1): 173–84. doi:10.1534/genetics.104.039420. PMC 1449730. PMID 15744048. 
  6. ^ 6.0 6.1 Lum, L.; Beachy, PA. The Hedgehog Response Network: Sensors, Switches, and Routers. Science. 2004, 304 (5678): 1755–9. doi:10.1126/science.1098020. PMID 15205520. 
  7. ^ Chen, W.; Ren, XR; Nelson, CD; Barak, LS; Chen, JK; Beachy, PA; De Sauvage, F; Lefkowitz, RJ. Activity-Dependent Internalization of Smoothened Mediated by -Arrestin 2 and GRK2. Science. 2004, 306 (5705): 2257–60. doi:10.1126/science.1104135. PMID 15618519. 
  8. ^ Alcedo, Joy; Zou, Yu; Noll, Markus. Posttranscriptional Regulation of Smoothened is Part of a Self-Correcting Mechanism in the Hedgehog Signaling System. Molecular Cell. 2000, 6 (2): 457–65. doi:10.1016/S1097-2765(00)00044-7. PMID 10983991. 
  9. ^ Apionishev, Sergey; Katanayeva, Natalya M.; Marks, Steven A.; Kalderon, Daniel; Tomlinson, Andrew. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nature Cell Biology. 2004, 7 (1): 86–92. doi:10.1038/ncb1210. PMID 15592457. 
  10. ^ Ho, K. S.; Suyama, K; Fish, M; Scott, MP. Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused. Development. 2005, 132 (6): 1401–12. doi:10.1242/dev.01689. PMID 15750186. 
  11. ^ Von Ohlen, T.; Lessing, D; Nusse, R; Hooper, JE. Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein. Proceedings of the National Academy of Sciences. 1997, 94 (6): 2404–9. doi:10.1073/pnas.94.6.2404. PMC 20100. PMID 9122207. 
  12. ^ Ingham, P. W.; McMahon, AP. Hedgehog signaling in animal development: Paradigms and principles. Genes & Development. 2001, 15 (23): 3059–87. doi:10.1101/gad.938601. PMID 11731473. 
  13. ^ Aspiras, A.C.; Prasad, R.; Fong, D.W.; Carlini, D.B.; Angelini, D.R. Parallel reduction in expression of the eye development gene hedgehog in separately derived cave populations of the amphipod Gammarus minus. Journal of Evolutionary Biology. 2012, 25: 995–1001. doi:10.1111/j.1420-9101.2012.02481.x. 

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参见[编辑]