Hypospadias is a defect in penis development that results in an abnormally placed urethral opening. It occurs in around 1/125 live male births in Australia, making it one of the most common congenital abnormalities in humans. The frequency of hypospadias is increasing worldwide and has been correlated with our increasing exposure to endocrine disrupting chemicals (EDCs). Despite its prevalence, relatively little is known about the causes of this common disease and, in particular, how EDCs affect urethral closure.
We have characterized a novel role for estrogen signaling in distal urethral development. We have also identified a hormonally responsive long non-coding RNA (lncRNA) Lnc353, which acts as a master regulator of urethral closure. Deletion of Lnc353 results in a complete failure of urethral closure. Lnc353 maps 230kb downstream of the EfnB2 gene and we have demonstrated a direct interaction between Lnc353 and the EfnB2 protein. Lnc353 binding affects EfnB2 autoregulation, which is critical for normal urethral closure. Exposure to estrogenic EDCs can decrease Lnc353 expression and may be a primary cause of hypospadias in humans. Furthermore, this novel hypospadias model has provided important new insights into the mechanisms regulating normal penile development and the causes of hypospadias.