Anorectal malformations caused by defects in sonic hedgehog signaling

Anorectal malformations are a common clinical problem affecting the develop ment of the distal hindgut in infants. The spectrum of anorectal malformati ons ranges from the mildly stenotic anus to imperforate anus with a fistula between the urinary and intestinal tracts to the most severe form, persist ent cloaca. The etiology, embryology, and pathogenesis of anorectal malform ations are poorly understood and controversial. Sonic hedgehog (Shh) is an endoderm-derived signaling molecule that induces mesodermal gene expression in the chick hindgut. However, the role of Shh signaling in mammalian hind gut development is unknown. Here, we show that mutant mice with various def ects in the Shh signaling pathway exhibit a spectrum of distal hindgut defe cts mimicking human anorectal. malformations. Shh null-mutant mice display persistent cloaca. Mutant mice lacking Gli2 or Gli3, two zinc finger transc ription factors involved in Shh signaling, respectively, exhibit imperforat e anus with recto-urethral fistula and anal stenosis. Furthermore, persiste nt cloaca is also observed in Gli2(-/-); Gli3(+/-), Gli2(+/-);Gli3(-/-), an d Gli2(-/-);Gli3(-/-) mice demonstrating a gene dose-dependent effect. Ther efore, Shh signaling is essential for normal development of the distal. hin dgut in mice and mutations affecting Shh signaling produce a spectrum of an orectal malformations that may reveal new insights into their human disease equivalents.