Immunohistochemical Characterization of Sonic Hedgehog and its Downstream Signaling Molecules During Human Penile Development

Abstract

Hypospadias is a common congenital anomalies, yet its molecular basis remains unknown. Recent studies have linked perturbations in the Hedgehog signaling pathway to hypospadias. However, the expression of Sonic hedgehog (Shh) has not been reported during genital development. Immunohistochemical staining for Shh and its receptors was applied to 10 human fetal penises ranging from 12 to 29 weeks gestation. The intensity of Shh staining was greatest in the urethral epithelium at 14 weeks gestation, correlating with the time of urethral tubularization. Results suggest a role for Shh in human male genital development.

Hedgehog signal disruption, gonadal dysgenesis and reproductive disorders: Is there a link to endocrine disrupting chemicals?

“…Recent studies in the same marsupial model have revealed a delicate spatiotemporal expression pattern of SHH and IHH during phallus development and it is clear that disrupted HH signaling can cause genital disorders such as hypospadias ( Tarulli et al, 1237 ). As for extrapolations to humans, HH signaling components are expressed in the phallus during urethral closure ( Shehata et al, 2011 ) and polymorphisms in HH-related genes are associated with a higher risk for boys being born with hypospadias ( Carmichael et al, 2013 ). These are not concrete cause-effect relationships, but HH signaling appear to be an evolutionary conserved signaling pathway critical for external genitalia development across mammalian species.…”

The Genetic and Environmental Factors Underlying Hypospadias

“…In the human foetal penis, SHH , PTCH1 , SMO , and GLI1 are all expressed around the time of urethral closure [Shehata et al, 2011], indicating that the role of this pathway is conserved. Variants in both SHH itself, and also in downstream components of its signalling pathway, have been associated with hypospadias in humans.…”

Expression patterns of Fgf8 and Shh in the developing external genitalia of Suncus murinus

“…For example, Shh is expressed in the cloacal and urethral epithelium of the GT and plays critical roles in both GT outgrowth initiation and mesenchymal differentiation of the GT (Haraguchi et al 2001, Perriton et al 2002, Miyagawa et al 2009a. SHH signalling is also involved in the patterning and development of the male urethra in humans (Shehata et al 2011). Our results indicate that SHH plays similar roles in the mouse and the suncus during GT development.…”