Meeting Abstract
Abnormalities of the external genitalia are among the most common birth defects in humans, affecting approximately 1/250 live births. Development of external genitalia begins with the emergence of paired genital swellings on either side of the embryonic cloaca. The genital swellings then merge to form the genital tubercle, the precursor of the penis and clitoris. Interactions between the endodermal urethral plate epithelium and the surrounding mesenchyme coordinate outgrowth and patterning of the external genitalia. Sonic hedgehog (Shh) is expressed in the urethral epithelium and plays an essential role in the growth of the genital tubercle. Deletion of Sonic hedgehog results in absence of external genitalia in mice, although Shh mutants still form the initial paired genital swellings, indicating that Shh is not required for initiation of genital outgrowth. In a characterization of the transcriptome of the urethral plate epithelium, we found that Indian hedgehog (Ihh), another hedgehog family member, is co-expressed with Shh. To determine if Ihh could compensate for the loss of Shh to promote initiation of genital swellings in Shh mutants, we conditionally deleted both Ihh and Shh in mice. Using 3D imaging (nanoCT) and cell lineage analysis, we found that the double knockout had a more severe genital phenotype than the Shh or Ihh mutants. Specifically, we show that Shh;Ihh homozygous conditional knockouts fail to initiate genital budding and have an expanded cloaca. Comparison of gene expression in Shh/Ihh single and double mutants shows that Ihh can partially compensate for Shh to activate the genital outgrowth circuit. Together these results indicate that coordinated activity of Shh and Ihh is required for initiation of external genital development in mice.
