Abstract
Ductal budding in the developing prostate is a testosterone-dependent event that involves signaling between the urogenital sinus epithelium (UGE) and urogenital sinus mesenchyme (UGM). We show here that ductal bud formation is associated with focused expression of Sonic hedgehog (Shh) in the epithelium of nascent prostate buds and in the growing tips of elongating prostate ducts. This pattern of localized Shh expression occurs in response to testosterone stimulation. The gene for the Shh receptor, Ptc1, is expressed in the UGM, as are the members of the Gli gene family of transcriptional regulators (Gli1, Gli2, and Gli3). Expression of Ptc1, Gli1, and Gli2 is localized primarily to mesenchyme surrounding prostate buds, whereas Gli3 is expressed diffusely throughout the UGM. A strong dependence of Gli1 (and Ptc1) expression on Shh signaling is demonstrated by induction of expression in both the intact urogenital sinus and the isolated UGM by exogenous SHH peptide. A similar dependence of Gli2 and Gli3 expression on Shh is not observed. Nonetheless, the chemical inhibitor of Shh signaling, cyclopamine, produced a graded inhibition of Gli gene expression (Gli1> Gli2> Gli3) in urogenital sinus explants that was paralleled by a severe inhibition of ductal budding.
Original language | English (US) |
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Pages (from-to) | 349-366 |
Number of pages | 18 |
Journal | Developmental Biology |
Volume | 249 |
Issue number | 2 |
DOIs | |
State | Published - 2002 |
Funding
We thank Dr. Matthew Scott (Stanford University School of Medicine) and Dr. Alexandra L. Joyner (New York University School of Medicine) for their generous gifts of cDNA plasmids used in our studies; Dr. Alfred W. Rademaker (Northwestern University Medical School) for his help with statistical analysis; and, Curis, Inc. (Cambridge, MA) for the generous supply of recombinant human SHH peptide. The monoclonal antibody 5E1 developed by T. M. Jessell was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. This work was supported by grants from the National Institutes of Health (DK 02426, DK 52687) and the National Institute of Environmental Health Sciences (PO1 ES10549).
Keywords
- Cyclopamine
- Ductal budding
- Gli
- Prostate development
- Ptc1
- Sonic hedgehog
- Urogenital sinus
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
- Cell Biology