（生物谷注：左邊黑色小箭頭所指為松果體,，右側(cè)白色箭頭指向肝臟,，黑箭頭指向胰腺）
北大生命科學(xué)院遺傳與發(fā)育中心細(xì)胞增殖與分化重點(diǎn)實(shí)驗(yàn)室，加州大學(xué)分子細(xì)胞發(fā)育生物學(xué)系,，加州大學(xué)Cedar-Sinai 研究所醫(yī)學(xué)系的研究人員以斑馬魚為模型,，在胰腺外分泌部分的研究方面取得新進(jìn)展，相關(guān)成果發(fā)布在11月的PLoS Biology上,。
胰腺內(nèi)分泌細(xì)胞以及外分泌細(xì)胞均來(lái)自胰十二指腸同源基因1（pancreatic-duodenal homeobox 1(pdx1)-positive progenitors)陽(yáng)性祖細(xì)胞系,。關(guān)于生物體如何控制祖細(xì)胞的分化命運(yùn)的分子機(jī)制一直了解不多。相比之下,， 內(nèi)分泌細(xì)胞的分化機(jī)制比外分泌細(xì)胞的分化機(jī)制要研究得深入些,。
在本研究中，研究小組獲得并鑒定出一種控制外分泌細(xì)胞分化的基因,，名為：外分泌細(xì)胞分化與增殖因子（exocrine differentiation and proliferation factor,exdpf),在斑馬魚模型中,，exdpf高度在祖細(xì)胞中表達(dá)這些祖細(xì)胞最終發(fā)育成胰腺。如果通過(guò)遺傳技術(shù)將exdpf敲除,，將導(dǎo)致外分泌細(xì)胞缺乏或分泌功能不足,，有趣的是外分泌細(xì)胞開始停止細(xì)胞周期，但是卻不發(fā)生凋亡,，外分泌細(xì)胞團(tuán)塊表面上看仍正常用RT-PCR鑒定發(fā)現(xiàn),，祖細(xì)胞細(xì)胞周期停滯是由細(xì)胞復(fù)制抑制基因p21cip與p27kip表達(dá)過(guò)度所致，并且cyclin G1也過(guò)度表達(dá),。但當(dāng)exdpf表達(dá)過(guò)高時(shí),，外分泌細(xì)胞增殖過(guò)速，導(dǎo)致內(nèi)分泌細(xì)胞增殖受阻,。這表明,，exdpf是外分泌細(xì)胞的促進(jìn)生長(zhǎng)調(diào)控機(jī)制，對(duì)內(nèi)分泌細(xì)胞而言是抑制基因,。
研究小組發(fā)現(xiàn)Ptf1a（pancrea-specific transcription factor 1a),，是促進(jìn)expdf轉(zhuǎn)錄的因子，有三個(gè)結(jié)合位點(diǎn)。而expdf的下游作用分子是維甲酸A（retinoic acid RA）,維甲酸是促進(jìn)胰腺發(fā)育的活性物質(zhì),。
研究小組這一成果為胰腺發(fā)育提供了新的研究思路,，找出了一種控制胰腺外分泌細(xì)胞發(fā)育的基因。這一基因在哺乳動(dòng)物中高度保守,，并且研究者還發(fā)現(xiàn)expdf在某些人類腫瘤組織中過(guò)度表達(dá),，這也許表明expdf是促進(jìn)腫瘤發(fā)生的基因之一。
該研究項(xiàng)目獲得中國(guó)973計(jì)劃支持,， 從及美國(guó)NIH的資助。（生物谷Bioon.com）
生物谷推薦原始出處：
PLoS Biol 6(11): e293 doi:10.1371/journal.pbio.0060293
Exdpf Is a Key Regulator of Exocrine Pancreas Development Controlled by Retinoic Acid and ptf1a in Zebrafish
Zhi Jiang1, Jianbo Song2, Fei Qi1, An Xiao1, Xizhou An1, Ning-ai Liu3, Zuoyang Zhu1, Bo Zhang1*, Shuo Lin1,2*
1 Key Laboratory of Cell Proliferation and Differentiation, Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Ministry of Education, Beijing, People's Republic of China,
2 Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, United States of America, 3 Department of Medicine, Cedars-Sinai Research Institute, University of California, Los Angeles, Los Angeles, California, United States of America
Both endocrine and exocrine pancreatic cells arise from pancreatic-duodenal homeobox 1 (pdx1)-positive progenitors. The molecular mechanisms controlling cell fate determination and subsequent proliferation, however, are poorly understood. Unlike endocrine cells, less is known about exocrine cell specification. We report here the identification and characterization of a novel exocrine cell determinant gene, exocrine differentiation and proliferation factor (exdpf), which is highly expressed in the exocrine cell progenitors and differentiated cells of the developing pancreas in zebrafish. Knockdown of exdpf by antisense morpholino caused loss or significant reduction of exocrine cells due to lineage-specific cell cycle arrest but not apoptosis, whereas the endocrine cell mass appeared normal. Real-time PCR results demonstrated that the cell cycle arrest is mediated by up-regulation of cell cycle inhibitor genes p21Cip, p27Kip, and cyclin G1 in the exdpf morphants. Conversely, overexpression of exdpf resulted in an overgrowth of the exocrine pancreas and a severe reduction of the endocrine cell mass, suggesting an inhibitory role for exdpf in endocrine cell progenitors. We show that exdpf is a direct target gene of pancreas-specific transcription factor 1a (Ptf1a), a transcription factor critical for exocrine formation. Three consensus Ptf1a binding sites have been identified in the exdpf promoter region. Luciferase assay demonstrated that Ptf1a promotes transcription of the exdpf promoter. Furthermore, exdpf expression in the exocrine pancreas was lost in ptf1a morphants, and overexpression of exdpf successfully rescued exocrine formation in ptf1a-deficient embryos. Genetic evidence places expdf downstream of retinoic acid (RA), an instructive signal for pancreas development. Knocking down exdpf by morpholino abolished ectopic carboxypeptidase A (cpa) expression induced by RA. On the other hand, exdpf mRNA injection rescued endogenous cpa expression in embryos treated with diethylaminobenzaldehyde, an inhibitor of RA signaling. Moreover, exogenous RA treatment induced anterior ectopic expression of exdpf and trypsin in a similar pattern. Our study provides a new understanding of the molecular mechanisms controlling exocrine cell specification and proliferation by a novel gene, exdpf. Highly conserved in mammals, the expression level of exdpf appears elevated in several human tumors, suggesting a possible role in tumor pathogenesis.
