EXPRESSION OF HUMAN GLI IN MICE RESULTS IN FAILURE-TO-THRIVE, EARLY DEATH, AND PATCHY HIRSCHSPRUNG-LIKE GASTROINTESTINAL DILATATION

Background: GLI is an oncodevelopmental gene in the vertebrate hedgeho g/patched signaling pathway chat is spatiotemporally regulated during development and is amplified in a subset of human cancers. GLI is the prototype for the Gli-Kruppel family of transcription factors, which i ncludes the Drosophila segment polarity gene ci, the C. elegans sex-de termining gene tra-l, and human and mouse GLI3, all of which contain a conserved domain of five C-2-H-2 zinc fingers. GLI3 mutations have be en implicated in the mouse mutant extra toes, as well as in human Grei g cephalopolydactaly syndrome and the autosomal dominant form of Palli ster-Hail syndrome. As such, GLI and the vertebrate hedgehog/patched s ignaling pathway appear to play important roles in both normal develop ment and neoplasia. Materials and Methods: Since it is not known whet her aberrant GLI expression is similarly linked to developmental disor ders, we developed gain-of-function transgenic mice which express huma n GLI ectopically. Results: Affected transgenic mice exhibit a phenoty pe of failure to thrive, early death, and Hirschsprung-like patches of gastrointestinal dilatation. The colons of affected mice have greatly attenuated smooth muscle layers and abnormal overlying epithelium. Th e density of myenteric plexuses is reduced in the colonic walls. The s everity of the phenotype is related to the level of transgene expressi on. Conclusions: The transgenic mouse model supports a role for GLI in gastrointestinal development. As parr of the vertebrate hedgehog/patc hed signaling pathway, GLI is essential to mesoderm and CNS ectoderm d evelopment and transgenic GLI expression affects neuronal, muscular, a nd epithelial cell differentiation in the gut. Expression of human GLI in mice results in impairment of enteric neuronal development and a H irschsprung-like phenotype.