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

Expression of human keratinocyte growth factor (KGF/FGF-7) was directe d to hepatocytes during the later period of mouse gestation using a hu man apolipoprotein E (ApoE) gene promoter and its associated liver-spe cific enhancer, Human KGF was detectable in liver extracts and serum p repared from e(17.5)-e(19.5) embryos, concomitant with the appearance of morphological abnormalities in several organs which express KGF rec eptor, The most striking phenotypic aberration in the ApoE-hKGF transg enic embryos was marked hyperplasia and cystic dilation of the cortica l and medullary kidney collecting duct system, a phenotype resembling infantile polycystic kidney disease in humans, Transgenic embryos had enlarged livers, with prominent biliary epithelial hyperplasia, and al so exhibited enhanced bronchiolar epithelial and type II pneumocyte pr oliferation, There was variable hyperplasia of intestinal epithelia, a nd urothelium of the urinary bladder and ureters, When compared to age -matched littermate controls, marked epidermal papillomatous acanthosi s and hyperkeratosis in the skin, with a notable decrease in the slumb er of developing hair follicles was seen in transgenic embryos, The pa ncreas exhibited significant ductal hyperplasia, with an increase in t he number of ductal epithelial cells staining positive for insulin exp ression, High systemic levels of KGF during the latter stages of embry ogenesis causes abnormalities in epithelial growth and differentiation within multiple organ systems and results in perinatal lethality, Cor rect temporal and spatial expression of KGF during the latter stages o f organ development is likely to play a critical role in mesenchymal-e pithelial signaling required for normal embryonic growth and developme nt.