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.