title: Differential stage-dependent regulation of prostatic epithelial morphogenesis by Hedgehog signaling.
abstract: Published studies of Hh (Hedgehog) signaling in the developing prostate have reported varying and discrepant effects on epithelial proliferation, ductal morphogenesis and growth. We report here that these differing observations accrue from stage-specific effects of Hh signaling in the developing prostate. Using in vitro organ cultures of the E16 UGS and P1 prostate, we show that ectopic Hh pathway activation stimulates epithelial proliferation prenatally, but inhibits epithelial proliferation postnatally. Extrapolating from previously published observations that Hh target gene expression is altered in the reactive stroma of prostate cancer, we examined and found discordant regulation of a subset of target genes by Hh signaling in the prenatal and postnatal prostate. Cell based studies and recombination assays show that these changes are not simply attributable to the age of the mesenchyme or the epithelium, but more likely reflect a complex regulation by the cellular microenvironment. To determine the in vivo relevance of these observations, we examined the effect of transgenic activation of Hh signaling on epithelial proliferation in the prenatal and postnatal prostate and confirmed the operation of stage-specific effects. These observations demonstrate stage-specific differences in the effect of Hh signaling on epithelial proliferation in the developing prostate and suggest that these are a product of complex interactions determined by the cellular microenvironment.
authors: Molecular and Environmental Toxicology Center, University of Wisconsin Medical School, Madison, WI 53705, USA.
authors: Min
authors: M
authors: Yu
authors: Wade
authors: W
authors: Bushman
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology*; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D009924:Organ Culture Techniques; D011467:Prostate / Q000196:embryology* / Q000254:growth & development*; D015398:Signal Transduction; D013997:Time Factors; D019076:Transgenes
chemical_list: D053823:Hedgehog Proteins
references: J Biol Chem. 2003 May 16;278(20):18506-13
references: 12626524
references: Dev Biol. 2002 Sep 15;249(2):349-66
references: 12221011
references: Diabetes. 2010 May;59(5):1211-21
references: 20185815
references: Dev Biol. 2003 Mar 15;255(2):238-48
references: 12648487
references: Prostate. 2006 Sep 15;66(13):1347-58
references: 16752376
references: FASEB J. 2004 Sep;18(12):1456-8
references: 15247143
references: FASEB J. 2004 Aug;18(11):1200-8
references: 15284220
references: Science. 2004 Feb 6;303(5659):848-51
references: 14764882
references: J Pediatr Surg. 1995 Sep;30(9):1273-81
references: 8523224
references: J Clin Invest. 2002 Aug;110(3):341-50
references: 12163453
references: Endocr Relat Cancer. 2009 Sep;16(3):795-808
references: 19509068
references: Connect Tissue Res. 2008;49(1):1-6
references: 18293172
references: Dev Biol. 2004 Mar 15;267(2):387-98
references: 15013801
references: J Biol Chem. 2009 Feb 27;284(9):5620-9
references: 19095649
references: Curr Opin Genet Dev. 2010 Aug;20(4):391-9
references: 20466536
references: Oncogene. 2008 Jul 10;27(30):4180-90
references: 18362893
references: Endocrinology. 2006 May;147(5):2112-21
references: 16469805
references: Dev Biol. 2003 Dec 15;264(2):352-62
references: 14651923
references: Dev Biol. 2001 Apr 15;232(2):301-14
references: 11401393
references: Dev Dyn. 1997 Apr;208(4):454-65
references: 9097018
references: Prostate. 1983;4(5):503-11
references: 6889194
references: Dev Biol. 2006 Jul 1;295(1):13-25
references: 16707121
references: Cancer Res. 2001 Jul 15;61(14):5511-6
references: 11454700
references: Dev Biol. 2004 Dec 15;276(2):280-300
references: 15581865
references: Dev Biol. 1999 May 1;209(1):28-39
references: 10208740
references: Int J Gastrointest Cancer. 2001;29(2):85-92
references: 12754391
references: Ann N Y Acad Sci. 1991;638:38-52
references: 1785812
references: Nat Med. 1996 May;2(5):534-9
references: 8616711
references: Dev Biol. 2007 Dec 1;312(1):217-30
references: 18028901
references: J Cell Physiol. 2007 Nov;213(2):326-30
references: 17708531
references: Biol Reprod. 1986 Jun;34(5):961-71
references: 3730488
references: Oncogene. 2009 Dec 17;28(50):4480-90
references: 19784071