GHF-1-PROMOTER-TARGETED IMMORTALIZATION OF A SOMATOTROPIC PROGENITOR-CELL RESULTS IN DWARFISM IN TRANSGENIC MICE
GHF-1-PROMOTER-TARGETED IMMORTALIZATION OF A SOMATOTROPIC PROGENITOR-CELL RESULTS IN DWARFISM IN TRANSGENIC MICE
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DOI：
10.1101/gad.7.4.683
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发表时间：
1993-04-01
影响因子：
10.5
通讯作者：
MELLON, PL
中科院分区：
文献类型：
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作者：
LEW, D;BRADY, H;MELLON, PL
在垂体发育过程中，同源结构域蛋白GHF-1是生长激素（GM）和催乳素（PRL）基因表达所必需的。GHF-1 mRNA可在GH-或prl表达细胞出现前数天检测到，这表明存在一种促生长祖细胞，其中GHF-1转录首先被激活。我们利用GHF-1调控区在转基因小鼠中靶向SV40 t抗原（Tag）的肿瘤发生，使这种细胞类型永生化。GHF-Tag转基因导致表达GHF-1而不表达GH或PRL的体适性祖细胞的发育困陷，导致侏儒症。来自转基因垂体肿瘤的永生化细胞系保持了嗜乳性体细胞祖细胞的特征，因为它们表达GHF-1 mRNA和蛋白，但不能激活GH或PRL转录。利用这些细胞，我们发现了一种增强子，它在发育的早期阶段激活GHF-1转录，但在代表发育后期的细胞或其他细胞类型中不活跃。这些实验不仅证明了利用细胞类型特异性转录因子基因的调控区域使发育祖细胞永生化的潜力，而且说明了这种模型系统在发育控制研究中的力量。
During pituitary development, the homeo domain protein GHF-1 is required for generation of somatotropes and lactotropes and for growth hormone (GM and prolactin (PRL) gene expression. GHF-1 mRNA is detectable several days before the emergence of GH- or PRL-expressing cells, suggesting the existence of a somatotropic progenitor cell in which GHF-1 transcription is first activated. We have immortalized this cell type by using the GHF-1 regulatory region to target SV40 T-antigen (Tag) tumorigenesis in transgenic mice. The GHF-Tag transgene caused developmental entrapment of somatotropic progenitor cells that express GHF-1 but not GH or PRL, resulting in dwarfism. immortalized cell lines derived from a transgenic pituitary tumor maintain the characteristics of the somato/lactotropic progenitor in that they express GHF-1 mRNA and protein yet fail to activate GH or PRL transcription.-Using these cells, we identified an enhancer that activates GHF-1 transcription at this early stage of development yet is inactive in cells representing later developmental stages of the somatotropic lineage or in other cell types. These experiments not only demonstrate the potential for immortalization of developmental progenitor cells using the regulatory regions from cell type-specific transcription factor genes but illustrate the power of such model systems in the study of developmental control.