再生醫(yī)學(xué)研究的一個(gè)重要課題是:清楚地了解干細(xì)胞是如何分化為特殊的器官和組織的.現(xiàn)在,加州大學(xué)的Santa Barbara為這一領(lǐng)域的研究增添了新的發(fā)現(xiàn),他的研究小組確定了果蠅中決定干細(xì)胞產(chǎn)生不同類型的子細(xì)胞的機(jī)制.這些結(jié)果被發(fā)布在今日的Proceedings of the National Academy of Sciences上.
果蠅是干細(xì)胞生物學(xué)研究的一個(gè)極好的模型.為了觀察自然環(huán)境中的干細(xì)胞,UCSB的分子,、細(xì)胞和發(fā)育生物學(xué)教授Denise Montell研究了果蠅的卵巢.通過(guò)這些工作,該小組闡明了卵泡細(xì)胞分化的最早期階段.“很明顯,簡(jiǎn)單動(dòng)物控制細(xì)胞行為的基本原理是保守的,即該原理也控制了人類的細(xì)胞行為.”她說(shuō)：“有太多的知識(shí)我們可以通過(guò)研究簡(jiǎn)單生物模型來(lái)了解.”
castor(Cas)基因編碼一個(gè)表達(dá)于濾泡干細(xì)胞(follicle stem cells, FSCs)中的結(jié)構(gòu)核蛋白.研究人員發(fā)現(xiàn)在胚胎發(fā)育過(guò)程中,Cas對(duì)產(chǎn)生特殊類型的大腦細(xì)胞起到了關(guān)鍵作用,并且?guī)椭S持了整個(gè)生命過(guò)程中的FSCs.“確定了果蠅中的這一重要蛋白質(zhì),我們就能夠檢測(cè)是否人類中該蛋白質(zhì)的同源物對(duì)干細(xì)胞及其子代也是重要的.”Montell說(shuō)：“我們對(duì)控制干細(xì)胞行為的分子了解的越多,就能更近一步地達(dá)到我們控制這些細(xì)胞的目標(biāo).”
她的研究小組將進(jìn)化保守的Cas基因與另外2個(gè)進(jìn)化保守的基因hedgehog (Hh)和eyes absent (Eya)置于一個(gè)基因回路中,用來(lái)決定特化細(xì)胞后代的命運(yùn).另外,他們還確定了Cas可以作為Hh信號(hào)的一個(gè)關(guān)鍵的,、組織特異的靶標(biāo),它不僅在維持FSC方面發(fā)揮關(guān)鍵作用,而且還幫助維持了FSC后代的多樣化.
Cas和Eya的互補(bǔ)模式揭示了早期發(fā)育階段極細(xì)胞和柄細(xì)胞的逐級(jí)分化.另外,它還提供了一個(gè)指示細(xì)胞命運(yùn)的標(biāo)記物,并闡明了FSC后代發(fā)生不同命運(yùn)的分子和細(xì)胞機(jī)制.
在早期分化過(guò)程中,卵泡細(xì)胞經(jīng)歷了雙項(xiàng)選擇.那些將變?yōu)樘鼗?xì)胞的卵泡細(xì)胞位于卵室的兩極,并接著變?yōu)閮煞N類型的細(xì)胞——極細(xì)胞和柄細(xì)胞.3種基因——Cas,Eya和Hh,以不同的組合發(fā)揮作用,有時(shí)會(huì)強(qiáng)制性的決定形成哪類細(xì)胞.Cas是極細(xì)胞和柄細(xì)胞完成細(xì)胞命運(yùn)所需的,而Eya是這些細(xì)胞命運(yùn)的一個(gè)負(fù)調(diào)控因子.Hh是Cas表達(dá)必需的,并且Hh信號(hào)對(duì)Eya的抑制是必要性的.
Montell解釋說(shuō)：“如果只得到了這些標(biāo)記物中的一種,你很難評(píng)估事情的發(fā)展情況.所有的細(xì)胞看起來(lái)都是一樣的,你沒(méi)辦法知道什么時(shí)候會(huì)發(fā)生什么事情.但是現(xiàn)在,我們能真實(shí)地了解到細(xì)胞如何獲得了不同的特性.”
Hh在胚胎發(fā)育,、成人體內(nèi)平衡,出生缺陷和癌癥等多方面發(fā)揮作用.Hh拮抗劑目前正在進(jìn)行臨床試驗(yàn),用以治療幾種類型的癌癥.但是由于Hh信號(hào)在如此多不同類型的細(xì)胞和組織都是重要的, 這一抑制劑的系統(tǒng)性傳遞可能會(huì)導(dǎo)致嚴(yán)重的副作用.因此確定必要的,、特定組織的Hh感受器可以更具體地識(shí)別治療目標(biāo).
有朝一日,有針對(duì)性的抑制Hh信號(hào)或許可以有效地治療和預(yù)防多種人類癌癥.（生物谷Bioon.com）
doi: 10.1073/pnas.1300725110
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Castor is required for Hedgehog-dependent cell-fate specification and follicle stem cell maintenance in Drosophila oogenesis
Yu-Chiuan Changa,1,Anna C.-C. Janga,b,1,Cheng-Han Linb, and Denise J. Montella,c,2
Asymmetric division of stem cells results in both self-renewal and differentiation of daughters. Understanding the molecules and mechanisms that govern differentiation of specific cell types from adult tissue stem cells is a major challenge in developmental biology and regenerative medicine. Drosophila follicle stem cells (FSCs) represent an excellent model system to study adult stem cell behavior; however, the earliest stages of follicle cell differentiation remain largely mysterious. Here we identify Castor (Cas) as a nuclear protein that is expressed in FSCs and early follicle cell precursors and then is restricted to differentiated polar and stalk cells once egg chambers form. Cas is required for FSC maintenance and polar and stalk cell fate specification. Eyes absent (Eya) is excluded from polar and stalk cells and represses their fate by inhibiting Cas expression. Hedgehog signaling is essential to repress Eya to allow Cas expression in polar and stalk cells. Finally, we show that the complementary patterns of Cas and Eya reveal the gradual differentiation of polar and stalk precursor cells at the earliest stages of their development. Our studies provide a marker for cell fates in this model and insight into the molecular and cellular mechanisms by which FSC progeny diverge into distinct fates.
