Tumorigenesis in transgenic mice in which the SV40 T antigen is driven by the brain-specific FGF1 promoter.
Gene expression can be manipulated by the introduction of a hybrid gene formed by linking a highly tissue-specific regulatory element to a gene whose expression might be expected to alter cellular function. Previously, we have shown that the human FGF1 gene contains four distinct tissue-specific promoters. In an effort to perturb the programming of proliferation and differentiation in a subset of neural cells, we have produced transgenic mice bearing the brain-specific promoter of the human FGF1 gene joined to the SV40 immediate early gene, which encodes the large T antigen. The resulting mice, and offspring from four individual lines, developed brain tumors that originated in the pontine gray, just rostral to the fourth ventricle. Tumors were moderately vascularized, as demonstrated by staining with both hematoxylin and eosin and antibodies to three different endothelial cell markers, but vessels were histologically normal. Scattered tumor foci were present as early as postnatal day 26; and affected animals died between 5 - 8 months of age. In mature animals, tumors lacked terminal differentiation markers for astrocytes (glial fibrillary acidic protein) or neurons (synaptophysin and neuron-specific enolase). However, they expressed high levels of proliferating cell nuclear antigen and vimentin, markers for proliferating cells. This immunophenotype is consistent with the tumor being at an early stage of differentiation. Therefore, these mice may provide a valuable tool for the study of tumorigenesis, replenishment and differentiation of neural stem cells.
Chiu
I M
IM
Department of Internal Medicine, The Ohio State University, Columbus, Ohio, OH 43210, USA.
Touhalisky
K
K
Liu
Y
Y
Yates
A
A
Frostholm
A
A
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics; D010375:Pedigree; D011149:Pons / Q000196:embryology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D019076:Transgenes; D014746:Vimentin / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D018809:Proliferating Cell Nuclear Antigen; D011993:Recombinant Fusion Proteins; D014746:Vimentin; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors