（注：左边黑色小箭头所指为松果体，右侧白色箭头指向肝脏，黑箭头指向胰腺）

北大生命科学院遗传与发育中心细胞增殖与分化重点实验室，加州大学分子细胞发育生物学系，加州大学Cedar-Sinai 研究所医学系的研究人员以斑马鱼为模型，在胰腺外分泌部分的研究方面取得新进展，相关成果发布在11月的PLoS Biology上。

胰腺内分泌细胞以及外分泌细胞均来自胰十二指肠同源基因1（pancreatic-duodenal homeobox 1(pdx1)-positive progenitors)阳性祖细胞系。关于生物体如何控制祖细胞的分化命运的分子机制一直了解不多。相比之下， 内分泌细胞的分化机制比外分泌细胞的分化机制要研究得深入些。

在本研究中，研究小组获得并鉴定出一种控制外分泌细胞分化的基因，名为：外分泌细胞分化与增殖因子（exocrine differentiation and proliferation factor,exdpf),在斑马鱼模型中，exdpf高度在祖细胞中表达这些祖细胞最终发育成胰腺。如果通过遗传技术将exdpf敲除，将导致外分泌细胞缺乏或分泌功能不足，有趣的是外分泌细胞开始停止细胞周期，但是却不发生凋亡，外分泌细胞团块表面上看仍正常用RT-PCR鉴定发现，祖细胞细胞周期停滞是由细胞复制抑制基因p21cip与p27kip表达过度所致，并且cyclin G1也过度表达。但当exdpf表达过高时，外分泌细胞增殖过速，导致内分泌细胞增殖受阻。这表明，exdpf是外分泌细胞的促进生长调控机制，对内分泌细胞而言是抑制基因。

研究小组发现Ptf1a（pancrea-specific transcription factor 1a)，是促进expdf转录的因子，有三个结合位点。而expdf的下游作用分子是维甲酸A（retinoic acid RA）,维甲酸是促进胰腺发育的活性物质。

研究小组这一成果为胰腺发育提供了新的研究思路，找出了一种控制胰腺外分泌细胞发育的基因。这一基因在哺乳动物中高度保守，并且研究者还发现expdf在某些人类肿瘤组织中过度表达，这也许表明expdf是促进肿瘤发生的基因之一。

该研究项目获得中国973计划支持， 从及美国NIH的资助。

推荐原始出处：

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.