The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins.
The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins.
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DOI：
10.1242/dev.119.4.1301
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发表时间：
1993-12
期刊：
影响因子：
4.6
通讯作者：
S. Ang;A. Wierda;David J. Wong;K. Stevens;S. Cascio;J. Rossant;K. Zaret
中科院分区：
文献类型：
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作者：
S. Ang;A. Wierda;David J. Wong;K. Stevens;S. Cascio;J. Rossant;K. Zaret
我们对哺乳动物最终内胚层发育的调控基因知之甚少；这一胚层产生肠上皮和各种其他细胞类型，如肝细胞，来源于肠道。发现大鼠肝细胞转录因子HNF3与果蝇叉头基因相似，叉头基因在果蝇肠道发育中起关键作用，使我们分离出含有HNF3/叉头（HFH）结构域的基因，这些基因在小鼠内胚层发育中表达。我们从胚胎cDNA文库中恢复了小鼠HNF3 β，发现该基因在原肠胚形成开始时首先在原始条纹的前部表达，在最终内胚层首先产生的区域。它的表达持续存在于小鼠等效Hensen淋巴结的轴向结构中，即最终的内胚层和脊索，以及发育中的神经管的腹侧区域。高度相关基因HNF3 α的表达似乎比HNF3 β晚，并首先在中线内胚层细胞中发现。随后在脊索、腹侧神经管和肠内胚层中出现与HNF3 β相似的表达模式。微尺度DNA结合分析显示，在每9.5天的中肠中可以检测到HNF3蛋白。在后期，HNF3 mrna和蛋白在内胚层来源的组织（如肝脏）中强烈表达。HNF3也是唯一已知的肝细胞富集转录因子，存在于高度去分化的肝细胞系中，该细胞系保留了向肝脏表型再分化的能力。综上所述，这些研究表明HNF3 α和HNF3 β参与了内胚层谱系的启动和维持。我们还发现了一个新的含有hfh的基因，HFH-E5.1，在原始条纹阶段在后外胚层和中胚层短暂表达，后来主要在神经管中表达。HFH- e5.1在结构和表达谱上与果蝇HFH基因FD4高度相似，这表明HFH家族成员在发育中具有不同的进化保守作用。
Little is known about genes that govern the development of the definitive endoderm in mammals; this germ layer gives rise to the intestinal epithelium and various other cell types, such as hepatocytes, derived from the gut. The discovery that the rat hepatocyte transcription factor HNF3 is similar to the Drosophila forkhead gene, which plays a critical role in gut development in the fly, led us to isolate genes containing the HNF3/forkhead (HFH) domain that are expressed in mouse endoderm development. We recovered mouse HNF3 beta from an embryo cDNA library and found that the gene is first expressed in the anterior portion of the primitive streak at the onset of gastrulation, in a region where definitive endoderm first arises. Its expression persists in axial structures derived from the mouse equivalent of Hensen's node, namely definitive endoderm and notochord, and in the ventral region of the developing neural tube. Expression of the highly related gene, HNF3 alpha, appears to initiate later than HNF3 beta and is first seen in midline endoderm cells. Expression subsequently appears in notochord, ventral neural tube, and gut endoderm in patterns similar to HNF3 beta. Microscale DNA binding assays show that HNF3 proteins are detectable in the midgut at 9.5 days p.c. At later stages HNF3 mRNAs and protein are expressed strongly in endoderm-derived tissues such as the liver. HNF3 is also the only known hepatocyte-enriched transcription factor present in a highly de-differentiated liver cell line that retains the capacity to redifferentiate to the hepatic phenotype. Taken together, these studies suggest that HNF3 alpha and HNF3 beta are involved in both the initiation and maintenance of the endodermal lineage. We also discovered a novel HFH-containing gene, HFH-E5.1, that is expressed transiently in posterior ectoderm and mesoderm at the primitive streak stage, and later predominantly in the neural tube. HFH-E5.1 is highly similar in structure and expression profile to the Drosophila HFH gene FD4, suggesting that HFH family members have different, evolutionarily conserved roles in development.