Anorectal malformations caused by defects in sonic hedgehog signaling

Area of Science:

• Developmental Biology
• Genetics
• Pediatric Surgery

Background:

• Anorectal malformations (ARMs) are common congenital defects impacting infant distal hindgut development.
• The precise etiology, embryology, and pathogenesis of ARMs remain poorly understood and debated.
• Sonic hedgehog (Shh) signaling, known to influence chick hindgut development, has an uncharacterized role in mammalian hindgut formation.

Purpose of the Study:

• To investigate the role of Sonic hedgehog (Shh) signaling in mammalian distal hindgut development.
• To determine if defects in Shh signaling pathways can replicate the spectrum of human anorectal malformations in a mouse model.
• To elucidate the genetic basis of anorectal malformations through the study of Shh signaling.

Main Methods:

• Generation and analysis of mutant mice with targeted defects in the Shh signaling pathway, including Shh null-mutants and mutants lacking Gli2 or Gli3 transcription factors.
• Phenotypic characterization of mutant mice to identify and classify distal hindgut defects.
• Evaluation of gene dose-dependent effects in compound Gli2 and Gli3 mutants.

Main Results:

• Mutant mice with defects in Shh signaling exhibited a range of distal hindgut anomalies mirroring human ARMs.
• Shh null-mutant mice presented with persistent cloaca, the most severe form of ARM.
• Mutations in Gli2 or Gli3 resulted in imperforate anus with recto-urethral fistula and anal stenosis, with compound mutants showing gene dose-dependent effects on persistent cloaca.

Conclusions:

• Sonic hedgehog (Shh) signaling is essential for the normal development of the distal hindgut in mice.
• Mutations affecting the Shh signaling pathway can induce a spectrum of anorectal malformations in mice, providing a relevant model for human ARMs.
• This study provides new insights into the pathogenesis of human anorectal malformations by highlighting the critical role of Shh signaling.