Anorectal Malformations Caused by Defects in Sonic Hedgehog Signaling

Abstract

Anorectal malformations are a common clinical problem affecting the development of the distal hindgut in infants. The spectrum of anorectal malformations ranges from the mildly stenotic anus to imperforate anus with a fistula between the urinary and intestinal tracts to the most severe form, persistent cloaca. The etiology, embryology, and pathogenesis of anorectal malformations 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 hindgut development is unknown. Here, we show that mutant mice with various defects in the Shh signaling pathway exhibit a spectrum of distal hindgut defects mimicking human anorectal malformations. Shh null-mutant mice display persistent cloaca. Mutant mice lacking Gli2 or Gli3, two zinc finger transcription factors involved in Shh signaling, respectively, exhibit imperforate anus with recto-urethral fistula and anal stenosis. Furthermore, persistent cloaca is also observed in Gli2 Anorectal malformations encompass a broad spectrum of congenital defects that frequently necessitates urgent surgical treatment in the newborn period, most often because of intestinal obstruction and sepsis. One of the most common anomalies, imperforate anus, has an incidence of 1 in 5000 and carries with it significant chronic morbidity, particularly with fecal incontinence. The most severe form of anorectal malformation, the cloacae, where distal intestinal and genitourinary tracts remain in a common channel, is much less common than imperforate anus (1 in 50,000) but has more significant serious longterm medical problems including gender assignment.

MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

“…Our findings herein that the FG and Lujan mutations in MED12 also elicit aberrant GLI3-dependent SHH signaling not only suggests an additional basis for cognitive dysfunction through altered brain development (30,31), but may further explain a broad range of clinically diverse non-CNS phenotypes associated with these syndromal disorders. In this regard, many of the digit, craniofacial, corpus callosal, and anorectal malformations that typify FG and/or Lujan syndromes are similarly observed, to varying extents, in congenital anomaly syndromes (GCPS and PHS) arising from mutations in GLI3 (14,32,33). Thus, mutagenic impairment of two interacting components within a common signaling pathway could serve to explain the phenotypic overlap observed in these monogenic syndromes.…”

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

“…SHH is expressed in the cloaca, hindgut, ureter and metanephros (17,21,22). The urothelium acts as a signalling centre, orchestrating the differentiation of associated smooth muscle through SHH secretion (22); down-regulation of SHH expression by retinoic acid administration (17) and nullmutation of the gene (23) in rodents cause anorectal malformations including persistent cloaca. Teratogen administration (8) and Shh mutation (22) can also cause animal kidneys to be hypoplastic and fused.…”

“…In addition, we screened three other genes, Sonic Hedgehog (SHH: 7q36), Ephrin B2 (EFNB2: 13q33) and Hepatocyte Nuclear Factor 1 β(HNF1β: 17cen-q21.3). As detailed in the Discussion, SHH (8,17,(21)(22)(23), EFNB2 (24) and HNF1β (25)(26)(27)(28)(29) are expressed in the developing renal, genital and alimentary tracts, and have been functionally implicated in the normal development of these structures.…”

Urorectal septum malformation sequence: Insights into pathogenesis

“…Gli2-/-mutant mice have imperforate anus and rectourethral fistula, whereas Gli3-/-mutant mice have anal stenosis and ectopic anal openings in which the hindgut opens into the urogenital sinus. Gli2-/-/Gli3ϩ/-compound mutants have persistent cloacal abnormalities, with thinner, multilayered cloacal membranes; in these mice, the hindgut joins the distal end of the ureter (Kimmel et al, 2000;Mo et al, 2001).…”