圍繞腸壁的環(huán)形肌一個眾所周知的功能就是產生腸蠕動,促進食物的推進,。而在果蠅體內,,它還有一個極為重要的功能,那就是維持腸上皮干細胞的自我更新,。這項干細胞研究的最新發(fā)現(xiàn)由北京生命科學研究所襲榮文博士帶領的課題組完成,,并在線刊登在9月21日的《自然》(Nature)雜志上。
襲榮文利用果蠅作為實驗模型,,在分子和細胞水平上證明了干細胞的微環(huán)境對干細胞的調控作用,。“環(huán)形肌構成了腸上皮干細胞的微環(huán)境。”他發(fā)現(xiàn),,環(huán)形肌分泌的信號因子維持著腸上皮干細胞的存在并控制著它的活性,。
他說,這種控制著果蠅腸上皮干細胞自我更新的叫做Wnt信號因子,,能夠穿越一薄層由細胞外基質組成的基底膜,,然后到達干細胞的表面,結合并激活干細胞膜上的受體,,隨之激活一系列下游成員和轉錄因子,,從而在轉錄水平上調控基因的表達和干細胞的自我更新。抑制Wnt信號通路上任何一個環(huán)節(jié)都會導致干細胞的分化和丟失,。相反,,Wnt信號通路的過量激活可以直接導致干細胞的積聚和腫瘤的發(fā)生。Wnt信號通路在哺乳動物和人身上也被認為是控制腸上皮干細胞自我更新的一個主要機制,。
此項發(fā)現(xiàn)證明了以果蠅作為一個模式來解析腸道干細胞調控機制的可行性,。果蠅在遺傳學上的優(yōu)勢將有助于進一步解析腸道干細胞的調節(jié)機制及腸道腫瘤等疾病的發(fā)生機制。另外,,該研究也揭示了一個嶄新的干細胞微環(huán)境結構,。環(huán)形肌作為微環(huán)境細胞并不與腸上皮干細胞直接接觸,而是被一層基底膜隔開,。干細胞散布在基底膜上,,并沒有局部區(qū)域的聚集。研究干細胞的調控機制,,對理解腫瘤等疾病的發(fā)生進而有針對性地制定干預措施,,以期達到治愈目的具有重要意義。(生物谷Bioon.com)
生物谷推薦原始出處:
Nature,,doi:10.1038/nature07329,,Guonan Lin,Rongwen Xi
Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells
Guonan Lin1,2, Na Xu2 & Rongwen Xi2
1 Graduate program, Peking union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
2 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
In the Drosophila midgut, multipotent intestinal stem cells (ISCs) that are scattered along the epithelial basement membrane maintain tissue homeostasis by their ability to steadily produce daughters that differentiate into either enterocytes or enteroendocrine cells, depending on the levels of Notch activity1, 2, 3. However, the mechanisms controlling ISC self-renewal remain elusive. Here we show that a canonical Wnt signalling pathway controls ISC self-renewal. The ligand Wingless (Wg) is specifically expressed in the circular muscles next to ISCs, separated by a thin layer of basement membrane. Reduced function of wg causes ISC quiescence and differentiation, whereas wg overexpression produces excessive ISC-like cells that express high levels of the Notch ligand, Delta. Clonal analysis shows that the main downstream components of the Wg pathway, including Frizzled, Dishevelled and Armadillo, are autonomously required for ISC self-renewal. Furthermore, epistatic analysis suggests that Notch acts downstream of the Wg pathway and a hierarchy of Wg/Notch signalling pathways controls the balance between self-renewal and differentiation of ISCs. These data suggest that the underlying circular muscle constitutes the ISC niche, which produce Wg signals that act directly on ISCs to promote ISC self-renewal. This study demonstrates markedly conserved mechanisms regulating ISCs from Drosophila to mammals. The identification of the Drosophila ISC niche and the principal self-renewal signal will facilitate further understanding of intestinal homeostasis control and tumorigenesis.