Distinct expression patterns of Sulf1 and Hs6st1 spatially regulate heparan sulfate sulfation during prostate development.
BACKGROUND
Prostate morphogenesis initiates in the urogenital sinus (UGS) with epithelial bud development. Sulfatase-1 (SULF1) inhibits bud development by reducing extracellular heparan sulfate (HS) 6-O sulfation and impairing FGF10 signaling by means of the ERK1/2 mitogen activated kinases.


RESULTS
We characterized the expression patterns of HS 6-O sulfation modifying enzymes in the developing prostate by in situ hybridization and showed that Sulf1 and Hs6st1 had overlapping but distinct expression domains. Notably, Hs6st1 was present while Sulf1 was excluded from the tips of elongating epithelial buds. This predicted relatively high HS 6-O sulfation at the tips of elongating epithelial buds that was confirmed by immunohistochemistry. The pattern of Sulf1 expression in the peri-mesenchymal epithelium matched predicted locations of bone morphogenetic protein (BMP) signaling. Exogenous BMP4 and BMP7 induced Sulf1 expression in the UGS, decreased epithelial HS 6-O sulfation, and reduced ERK1/2 activation in response to FGF10.


CONCLUSIONS
These data suggest that BMPs limit FGF10 action in the developing prostate at least in part by inducing Sulf1.
Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Rita A
RA
Buresh-Stiemke
Rita L
RL
Malinowski
Kimberly P
KP
Keil
Chad M
CM
Vezina
Arie
A
Oosterhof
Toin H
TH
Van Kuppevelt
Paul C
PC
Marker
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000166:cytology / Q000196:embryology*; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics
D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D051526:Fibroblast Growth Factor 10; D006497:Heparan Sulfate; D048052:Mitogen-Activated Protein Kinase 3; D015238:Sulfotransferases; C525810:Bmp4 protein, mouse; C496464:Fgf10 protein, mouse; C525820:bmp7 protein, mouse; C485756:Hs6st1 protein, mouse; C486773:Sulf1 protein, mouse