Induction of Urothelial Cell Proliferation by Fibroblast Growth Factor-7 in RAG1-Deficient Mice
Fibroblast growth factor-7 (FGF-7, keratinocyte growth factor, KGF) is a 163 amino acid glycoprotein synthesized and secreted by mesenchymal cells (e.g. fibroblasts/ fibrocytes) in epithelial organs, thereby functioning as a paracrine mediator of epithelial cell proliferation. In the urinary bladder, FGF-7 is transported from the lamina propria across the urothelial basement membrane to where it ultimately binds to splice variants of the FGFR2 receptor present on the basolateral surface of transitional epithelial cells. We administered 100 μg/ml (LP.) recombinant FGF-7 (rFGF-7) to RAG1-deficient mice (n=3) for 7 days and observed a striking expansion of the urinary bladder urothelium. This expansion was characterized by a layer of stratified urothelium >20 cells thick and by positive immunostaining for the proliferation marker Ki-67. In contrast, RAG1-deficient mice (n=3) that received only buffer injection did not exhibit detectable urothelial expansion. rFGF-7 was detected by immunoblot analyses in the serum, but not in the urine, from RAG1-deficient mice that received the recombinant protein. Mice that have a targeted disruption in the gene encoding the V(D)J recombination activation gene RAG1 have small lymphoid organs with no mature B and T lymphocytes, due to the inability of cell progenitors to perform V(D)J recombination. The biological activity of FGF-7 in RAG-1 mice indicates that immuno-dependent mechanisms are not required for the induction of urothelial cell proliferation by this epithelial cell-specific growth factor.
KeywordsUrothelial Cell Keratinocyte Growth Factor Bladder Urothelium Nephron Number Partial Outlet Obstruction
Unable to display preview. Download preview PDF.
- 2.Baskin LS, Hayward SW, Sutherland RA, DiSandro MJ, Thomson AA, Goodman J, et al: Mesenchymal-epithelial interactions in the bladder. World J Urol, 14:301, 1995.Google Scholar
- 11.Jeffs RD: In: O’Donnell B, Koff SA, editors. Pediatric Urology, 3rd edition. Oxford: Butterworth-Heinemann; p. 540–541, 1997.Google Scholar
- 20.Neubauer BL, Chung LW, McCormick KA, Taguchi O, Thompson TC, Cunha GR: Epithelial-mesenchymal interactions in prostatic development. II. Biochemical observations of prostatic induction by urogenital sinus mesenchyme in epithelium of the adult rodent urinary bladder. J Cell Biol, 96:1671, 1983.PubMedCrossRefGoogle Scholar
- 21.Nguyen HQ, Danilenko DM, Bucay N, DeRose ML, Van GY, Thomason A, et al: Expression of keratinocyte growth factor in embryonic liver of transgenic mice causes changes in epithelial growth and differentiation resulting in polycystic kidneys and other organ malformations. Oncogene, 12:2109, 1996.PubMedGoogle Scholar
- 23.Qiao J, Uzzo R, Obara-Ishihara T, Degenstein L, Fuchs E, Herzlinger, D: FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Dev Suppl, 126:547, 1999.Google Scholar
- 26.Schluter C, Duchrow M, Wohlenberg C, Becker MH, Key G, Flad HD, et al: The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol, 123:513, 1993.PubMedCrossRefGoogle Scholar