刺猬信号通路

刺蝟信號通路（英語：Hedgehog signaling pathway）是重要的信號傳導通路。
刺蝟信號通路是動物發育的關鍵調控之一，在所有的兩側對稱動物中都有表達。刺蝟信號通路得名於在其多肽配體——Drosophila果蠅中發現的一種名為Hh的細胞間信號分子。Hh是 Drosophila體節極性基因的表達物，是果蠅體形發育形成的基礎。該分子在後期胚胎開成及變態期及起重要作用。。
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）。僅在魚類中發現有EHH和TwHH，哺乳類和其他動物中沒有這兩種刺蝟因子。
哺乳動物有三種刺蝟信號路徑同系物，DHH、IHH及SHH,其中Sonic研究得最深入。該路徑在脊椎動物胚胎發育中同樣的重要。缺乏該路徑組件的基因敲除小鼠，其大大腦、骨骼、肌肉系統、胃腸道及肺都未能正正常發育。近期研究表明刺蝟信號路徑在調節對成人組織起到維護及再生作用的成體幹細胞中的作用。同樣該路徑也與某些癌症的發生的關係。幾家製藥公司正在積極地開發針對刺蝟信號傳導以對抗癌症的藥物。

發現

在20世紀70年代，發育生物學的基本問題是一個相對簡單的受精卵是如何發展成一個複雜的身體分節的動物的。70年代末，克里斯汀·紐斯林-沃爾哈德和艾瑞克·威斯喬斯分離了控制果蠅前後體軸發育分節的突變基因，他們的「飽和誘變」技術導致了一系列參與體軸形態發生基因的發現。1995年，他們因在對果蠅胚胎發育基因突變的研究工作與愛德華·路易斯共同獲得諾貝爾獎。 
黑腹果蠅的刺蝟 (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。刺蝟基因的功能為影響體節極性，其突變會會影響幼體的表皮棘刺和成體的附支，如腿和觸角。Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). 刺蝟基因突變的果蠅幼蟲具有短小且多毛的特徵，形似刺蝟，故此得名。

機制

昆蟲細胞表達全長含有鋅指的轉錄因子Ci蛋白, 而此蛋白會在細胞質中和類似kinesin蛋白Costal-2 (Cos2) 形成複合體並結合到微管上（圖2）。 SCF複合物對155 kDa全長Ci蛋白的依賴於蛋白酶體的剪切產生75 kDa片段(CiR)。CiR在細胞內累計並擴散到細胞核，在那裡它作為刺蝟因子靶基因的共抑制物。 The steps leading to Ci protein proteolysis include phosphorylation of Ci protein by several protein kinases; PKA, GSK3β and CK1 (Figure 2). 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 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. 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. It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels.
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. 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.

作用

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.
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 
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.

人類疾病

胚胎發育時缺少刺蝟因子（因基因突變或孕婦誤食致畸劑）都會導致嚴重的發育異常。