Sonic hedgehog induces prostate development by activating a cascade of developmental factors. This application will characterize and test a postulated mechanism for the induction of normal human prostate development. Benign enlargement of the prostate gland in aging men occurs by focal, progressive growth. It displays a variegated histology and complex architecture that mimics normal prostate morphogenesis. My study of fetal prostate development will provide novel insights into a possible mechanism for benign hyperplastic growth in the adult and suggest new approaches to prevent and arrest abnormal growth. The prostate is an exocrine gland composed of a complex ductal system enmeshed in a supporting stroma. During fetal prostate development the ductal system is formed by outgrowths of urogenital sinus epithelium (UGS) into a surrounding mesenchyme. Testosterone stimulates prostate development, but the molecular mechanisms which initiate ductal outgrowth remain unknown. A highly conserved mechanism of induction that operates in embryonic development of many different organ systems involves a developmental cascade induced by the product of the gene sonic hedgehog (Shh). The Shh catalyzes development by activating expression of several downstream genes which regulate cell proliferation, apoptosis, and morphogenesis. The Shh initiates and maintains expression of fibroblast growth factors; it induces TGF beta-related bone morphogenetic proteins; and it activates expression of specific Hox genes. I will present preliminary evidence that this highly conserved inductive mechanism also initiates prostate development: 1) the Shh is expressed in the UGS during the period of prostate induction and expression correlates with prostate ductal budding; 2) prostate development is blocked by the presence of Shh-antibody; and 3) three likely targets of Shh regulation, including keratinocyte growth factor (FGF-7), bone morphogenetic protein (BMP-4), and Hox-d13 are all expressed in the fetal prostate. I postulate that Shh induces prostate development by activating expression of FGF-7, BMP-4, and Hox-d13. I will use quantitative assays for gene expression and localization studies to correlate expression of Shh with regulation of expression of FGF-7, BMP-4, and Hox-d13 in the developing prostate. I will experimentally test the ability to induce prostate development and activate expression of FGF-7, BMP-4, and Hox-d13. Finally, I will examine the growth related effects of FGF-7 and BMP-4 in the developing prostate by quantitatively assaying the effect of locally applied FGF-7 and BMP-4 on epithelial and mesenchymal proliferation and apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052687-02
Application #
2713462
Study Section
Special Emphasis Panel (SRC (05))
Project Start
1997-07-07
Project End
2001-05-31
Budget Start
1998-06-20
Budget End
1999-05-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Cook, Crist; Vezina, Chad M; Allgeier, Sarah H et al. (2007) Noggin is required for normal lobe patterning and ductal budding in the mouse prostate. Dev Biol 312:217-30
Shi, Xudong; Gipp, Jerry; Bushman, Wade (2007) Anchorage-independent culture maintains prostate stem cells. Dev Biol 312:396-406
Doles, Jason; Cook, Crist; Shi, Xudong et al. (2006) Functional compensation in Hedgehog signaling during mouse prostate development. Dev Biol 295:13-25
Doles, J D; Vezina, C M; Lipinski, R J et al. (2005) Growth, morphogenesis, and differentiation during mouse prostate development in situ, in renal grafts, and in vitro. Prostate 65:390-9
Lamm, Marilyn L; Catbagan, Winnie S; Laciak, Robert J et al. (2002) Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev Biol 249:349-66
Barnett, Daniel H; Huang, Hong-Ying; Wu, Xue-Ru et al. (2002) The human prostate expresses sonic hedgehog during fetal development. J Urol 168:2206-10
Lamm, M L; Podlasek, C A; Barnett, D H et al. (2001) Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate. Dev Biol 232:301-14
Podlasek, C A; Seo, R M; Clemens, J Q et al. (1999) Hoxa-10 deficient male mice exhibit abnormal development of the accessory sex organs. Dev Dyn 214:1-12
Podlasek, C A; Barnett, D H; Clemens, J Q et al. (1999) Prostate development requires Sonic hedgehog expressed by the urogenital sinus epithelium. Dev Biol 209:28-39
Podlasek, C A; Clemens, J Q; Bushman, W (1999) Hoxa-13 gene mutation results in abnormal seminal vesicle and prostate development. J Urol 161:1655-61