Sonic hedgehog Cascade Is Required for Penile Postnatal Morphogenesis, Differentiation, and Adult Homeostasis1

Abstract

The penis is unique in that it undergoes morphogenesis and differentiation primarily in the postnatal period. For complex structures such as the penis to be made from undifferentiated precursor cells, proliferation, differentiation, and patterning are required. This process involves coordinated activity of multiple signals. Sonic hedgehog (Shh) forms part of a regulatory cascade that is essential for growth and morphogenesis of many tissues. It is hypothesized that the penis utilizes regulatory mechanisms similar to those of the limb and accessory sex organs to pattern penile postnatal morphogenesis and differentiation and that the Shh cascade is critical to this process. To test this hypothesis, Shh, BMP-4, Ptc, and Hoxa-10 localization and function were examined in Sprague-Dawley rat penes by means of quantitative reverse transcription polymerase chain reaction, in situ hybridization, immunohistochemistry, and Western blotting. These genes were expressed in the penis during postnatal morphogenesis in a spatially and temporally restricted manner in adjacent layers of the corpora cavernosal sinusoids. The function of Shh and BMP-4 is to establish and maintain corpora cavernosal sinusoids. The data suggest that Ptc and Hoxa-10 are also important in penile morphogenesis. The continuing function of Shh and targets of its signaling in maintaining penile homeostasis in the adult is significant because disruption of Shh signaling affects erectile function. This is the first report that demonstrates the significant role that Shh plays in establishing and maintaining penile homeostasis and how this relates to erectile function. These studies provide valuable insight that may be applied to improve treatment options for erectile dysfunction.

Molecular genetic cascades for external genitalia formation: An emerging organogenesis program

“…Such a dual mode of the Shh function in organogenesis would be a Dobyns et al (1999) unique aspect of Shh signaling in comparison with other organs. Furthermore, the possibility of the expression of a set of genes and growth factors, such as Shh, for the late stage male urethra or the cavernous body formation has been proposed and awaits further analysis (Podlasek et al, 2003a). It has been speculated that defects in maternal glucose or other metabolic abnormalities including cholesterol alterations may lead to embryonic defects with hedgehog pathways (Podlasek et al, 2003b).…”

755 Peptide Amphiphile Nanofiber Delivery of Sonic Hedgehog Protein to Reduce Smooth Muscle Apoptosis in the Penis After Cavernous Nerve Resection

“…Immunohistochemical (IHC) was performed as previously outlined [14][15][16] on penis tissue assayed with goat polyclonal anti-SHH (1/100, N-19, SC-1194, Santa Cruz) and antipatched (PTCH1, 1/100, G-19, SC-6149, Santa Cruz), and mouse monoclonal anti-cluster differentiation protein three (CD3, 1/50, SC-52382). The secondary antibodies used were Alexa Fluor 488 chicken antigoat (1/300, Molecular Probes, Carlsbad, CA), and Alexa Fluor 488 chicken anti-mouse (1/200, Molecular Probes).…”

“…The protein that we would like to utilize PA methodology to deliver to the corpora cavernosa of the penis is the secreted glycoprotein Sonic hedgehog (SHH), which is an essential regulator of penile smooth muscle and apoptosis that is critical for normal erectile function [14][15][16][17]. SHH is synthesized as a 45-49 kDa secreted precursor that undergoes autoproteolytic cleavage to yield two mature proteins: a19-kDa amino-terminal fragment which is cholesterol modified, palmitoylated, and is biologically active, and a 25-31 kDa carboxy-terminal fragment that retains no known biological activity [18][19][20].…”

“…SHH is necessary during embryogenesis of the penis for both genital tubercle outgrowth and differentiation [21] and in mice with a targeted deletion of Shh, external genitalia were completely absent [22]. The SHH pathway functions after birth to direct differentiation of corpora cavernosal sinuses [15] and in the adult penis SHH functions to maintain the sinusoid morphology of the corpora cavernosa [15] that it helped establish. When SHH signaling is inhibited in the adult penis, there is a significant 12-fold increase in smooth muscle apoptosis [14], which alters sinusoidal morphology and which causes ED [15].…”

“…The SHH pathway functions after birth to direct differentiation of corpora cavernosal sinuses [15] and in the adult penis SHH functions to maintain the sinusoid morphology of the corpora cavernosa [15] that it helped establish. When SHH signaling is inhibited in the adult penis, there is a significant 12-fold increase in smooth muscle apoptosis [14], which alters sinusoidal morphology and which causes ED [15]. In previous studies, it has been shown that SHH protein is decreased in the penis of two commonly studied rat models of ED, the BioBreeding/Worcester (BB/WOR) diabetic rat [16] and the CN-injured Sprague Dawley rat [14].We have recently shown the efficacy of apoptosis suppression in rats when SHH protein is delivered locally to the penis at the time of CN injury [14], indicating that SHH has significant potential to be developed as a treatment to prevent ED by suppressing post prostatectomy apoptosis.…”