Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 966-977 |
| Number of pages | 12 |
| Journal | Genes and Development |
| Volume | 13 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 1999 |
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Keywords
- Bulbourethral gland
- Haploinsufficiency
- Hyperplasia/dysplasia
- Organogenesis
- Prostate
- Tumor suppressor gene
ASJC Scopus subject areas
- Genetics
- Developmental Biology
Cite this
Roles for Nkx3.1 in prostate development and cancer. / Bhatia-Gaur, Rajula; Donjacour, Annemarie A.; Sciavolino, Peter J.; Kim, Minjung; Desai, Nishita; Young, Peter; Norton, Christine R.; Gridley, Thomas; Cardiff, Robert; Cunha, Gerald R.; Abate-Shen, Cory; Shen, Michael M.
In: Genes and Development, Vol. 13, No. 8, 15.04.1999, p. 966-977.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Roles for Nkx3.1 in prostate development and cancer
AU - Bhatia-Gaur, Rajula
AU - Donjacour, Annemarie A.
AU - Sciavolino, Peter J.
AU - Kim, Minjung
AU - Desai, Nishita
AU - Young, Peter
AU - Norton, Christine R.
AU - Gridley, Thomas
AU - Cardiff, Robert
AU - Cunha, Gerald R.
AU - Abate-Shen, Cory
AU - Shen, Michael M.
PY - 1999/4/15
Y1 - 1999/4/15
N2 - 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.
AB - 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.
KW - Bulbourethral gland
KW - Haploinsufficiency
KW - Hyperplasia/dysplasia
KW - Organogenesis
KW - Prostate
KW - Tumor suppressor gene
UR - http://www.scopus.com/inward/record.url?scp=0033561173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033561173&partnerID=8YFLogxK
U2 - 10.1101/gad.13.8.966
DO - 10.1101/gad.13.8.966
M3 - Article
C2 - 10215624
AN - SCOPUS:0033561173
VL - 13
SP - 966
EP - 977
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 8
ER -