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Vol. 13, No. 8, pp. 966-977, April 15, 1999
1 Center for Advanced Biotechnology and Medicine,
2 Department of Neuroscience and Cell Biology and
3 Department of Pediatrics, University of Medicine and
Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School,
Piscataway, New Jersey 08854 USA; 4 Department of Anatomy,
University of California, San Francisco, California 94143 USA;
5 The Jackson Laboratory, Bar Harbor, Maine 04609 USA;
6 Department of Pathology, School of Medicine, University of
California, Davis, California 95616 USA
In aging men, the prostate gland becomes hyperproliferative and
displays a propensity toward carcinoma. Although this
hyperproliferative process has been proposed to represent an
inappropriate reactivation of an embryonic differentiation program, the
regulatory genes responsible for normal prostate development and
function are largely undefined. Here we show that the murine
Nkx3.1 homeobox gene is the earliest known marker of prostate
epithelium during embryogenesis and is subsequently expressed at all
stages of prostate differentiation in vivo as well as in tissue
recombinants. A null mutation for Nkx3.1 obtained by targeted
gene disruption results in defects in prostate ductal morphogenesis and
secretory protein production. Notably, Nkx3.1 mutant mice
display prostatic epithelial hyperplasia and dysplasia that increases
in severity with age. This epithelial hyperplasia and dysplasia also
occurs in heterozygous mice, indicating haploinsufficiency for this
phenotype. Because human NKX3.1 is known to map to a prostate
cancer hot spot, we propose that NKX3.1 is a prostate-specific
tumor suppressor gene and that loss of a single allele may predispose
to prostate carcinogenesis. The Nkx3.1 mutant mice provide a
unique animal model for examining the relationship between normal
prostate differentiation and early stages of prostate carcinogenesis.
[Key Words: prostate; bulbourethral gland; organogenesis; hyperplasia/dysplasia; haploinsufficiency; tumor suppressor gene]
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 P. S. Nelson, C. Pritchard, |
