GHF-1-promoter-targeted immortalization of a somatotropic progenitor cell results in dwarfism in transgenic mice.
During pituitary development, the homeo domain protein GHF-1 is required for generation of somatotropes and lactotropes and for growth hormone (GH) 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.
Lew
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Department of Reproductive Medicine, University of California, San Diego, School of Medicine, La Jolla 92093.
Brady
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Klausing
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Yaginuma
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Theill
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Stauber
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Karin
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Mellon
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PL
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004393:Dwarfism, Pituitary / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D013006:Growth Hormone / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010903:Pituitary Gland, Anterior / Q000196:embryology*; D010911:Pituitary Neoplasms / Q000235:genetics; D013234:Stem Cells; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D013006:Growth Hormone; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494185:Pou1f1 protein, mouse