Sulfatase 1 Is an Inhibitor of Ductal Morphogenesis with Sexually Dimorphic Expression in the Urogenital Sinus

Abstract

The prostate gland develops from the urogenital sinus in response to circulating androgens. Androgens initiate and stimulate branching morphogenesis in the urogenital sinus via unknown mediators. Heparan sulfate proteoglycans are important extracellular molecules that sequester many growth factors in the extracellular matrix and facilitate signaling by some growth factors as part of ternary complexes that include growth factors, receptors, and heparan sulfate chains. Several enzymes modify the chemical structure of heparan sulfate to further regulate its activity. An examination of these enzymes for sexually dimorphic expression in the urogenital sinus identified Sulfatase 1 (Sulf1) as an enzyme that was down-regulated in the male urogenital sinus coincident with the initiation of prostatic morphogenesis. Down-regulation of Sulf1 was accompanied by an increase in the most highly sulfated forms of heparan sulfate, and a similar increase was observed in female urogenital sinuses treated with testosterone. Inhibiting de novo sulfation of heparan sulfate blocked prostatic morphogenesis, supporting the importance of heparan sulfate modification for prostate development. To functionally test the specific role of Sulf1 during prostate development, Sulf1 was ectopically expressed in the urogenital sinus. It partially inhibited testosterone-stimulated ductal morphogenesis, and it reduced the activation of fibroblast growth factor receptors as well as the ERK1 and ERK2 MAPKs. These data identify sulfatase 1 as an inhibitor of prostatic branching morphogenesis and growth factor signaling that is down-regulated as part of the normal response to androgen action in the male urogenital sinus.

Differential effects of estrogen exposure on arylsulfatase B, galactose-6-sulfatase, and steroid sulfatase in rat prostate development

“…The enzyme iduronate 2-sulfatase, which removes 2-sulfate groups from iduronate residues of HS or heparin, was one of 13 genes overexpressed in 16-month-old rat ventral prostate tissue compared with three-month-old rat tissue, suggesting a role in aging prostate tissue [36]. In cultured urogenital sinus (UGS) tissues from mouse embryos at different stages of development, expression of Sulfatase 1 (Sulf1), the enzyme that catalyses the hydrolysis of 6-O sulfates from heparan sulfate, was significantly decreased in male compared to female UGS as development progressed [37, 38]. This decrease was correlated with morphological changes in prostatic epithelial bud outgrowth, and interruption of HS 6-sulfation by ectopic expression of Sulf1 partially inhibited the testosterone-induced ductal morphogenesis and impaired FGF10 signaling.…”

Recent advances in prostate development and links to prostatic diseases

“…Organ culture : UGS tissues isolated and cultured in vitro are useful for studying branching morphogenesis, but they do not undergo differentiation 37. Transfection of the UGS followed by in vitro culture can be used to assess the effects of overexpression or knockdown of particular genes in development 27. Recent studies used in vitro UGS culture to identify factors that promote and inhibit prostate development.…”

Visualization and quantification of mouse prostate development by in situ hybridization

“…We and others have quantified prostate development by visualizing and counting the number of prostatic buds and branches formed in vivo and in vitro (Allgeier et al, 2010; Buresh et al, 2010; Lin et al, 2003; Timms, 2008). Several methods have been developed for this purpose, including light microscopy (Price, 1963), scanning electron microscopy (Lin et al, 2003), confocal microscopy (Buresh et al, 2010) and three dimensional serial reconstruction of UGS histological sections (Timms et al, 1994; Timms, 2008).…”

“…Several methods have been developed for this purpose, including light microscopy (Price, 1963), scanning electron microscopy (Lin et al, 2003), confocal microscopy (Buresh et al, 2010) and three dimensional serial reconstruction of UGS histological sections (Timms et al, 1994; Timms, 2008). All of these methods are capable of visualizing buds arising from the UGS and urethra and all have advantages and disadvantages.…”