Fibroblast growth factor 10 (Fgf10) invalidation results in anorectal malformation in mice

Background/Purpose: Anorectal malformations occur in 1 per 4,000 live births and represent a surgical challenge. Although critically important, the basic mechanisms of normal anorectal union are incompletely understood. Fgf10 signaling is known to serve a key role in mesenchymal/epithelial interactions in many organ systems including the gastrointestinal tract (GIT). The authors therefore hypothesized that Fgf10 signaling has a central role in normal anorectal development. Methods: Fgf10 expression in wild-type (Wt) embryos was evaluated using whole-mount in situ hybridization, Wt and Fgf10(-/-) embryos were harvested from timed pregnant mothers at E12.5 through E17.5 and were analyzed for anorectal phenotype. Results: Wt development of union between anorectal structures is completed between E12.5 and E13.5 with luminal communication between distal rectal epithelium and anus. Fgf10 is discreetly expressed at E12.5 in the distal rectum. Fgf10(-/-) mutants show failure of union of the rectum and anus at an early stage (E13.5) and near term (E17.5). Conclusions: Fgf10 is expressed in the rectum at the time when anorectal continuity is established, indicating a role in normal anorectal development. Fgf10 invalidation (Fgf10(-/-) mutant) results in a genetically reproducible anorectal malformation phenotype. Fgf10 function is critical for normal anorectal development.