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 hedgehog/patched signaling pathway that 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 includes the Drosophila segment polarity gene ci, the C. elegans sex-determining gene tra-1, and human and mouse GLI3, all of which contain a conserved domain of five C2-H2 zinc fingers. GLI3 mutations have been implicated in the mouse mutant extra toes, as well as in human Greig cephalopolydactaly syndrome and the autosomal dominant form of Pallister-Hall syndrome. As such, GLI and the vertebrate hedgehog/patched signaling pathway appear to play important roles in both normal development and neoplasia.


METHODS
Since it is not known whether aberrant GLI expression is similarly linked to developmental disorders, we developed gain-of-function transgenic mice which express human GLI ectopically.


RESULTS
Affected transgenic mice exhibit a phenotype 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. The density of myenteric plexuses is reduced in the colonic walls. The severity of the phenotype is related to the level of transgene expression.


CONCLUSIONS
The transgenic mouse model supports a role for GLI in gastrointestinal development. As part of the vertebrate hedgehog/patched signaling pathway, GLI is essential to mesoderm and CNS ectoderm development and transgenic GLI expression affects neuronal, muscular, and epithelial cell differentiation in the gut. Expression of human GLI in mice results in impairment of enteric neuronal development and a Hirschsprung-like phenotype.
Yang
J T
JT
Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, USA.
Liu
C Z
CZ
Villavicencio
E H
EH
Yoon
J W
JW
Walterhouse
D
D
Iannaccone
P M
PM
D000818:Animals; D015139:Blotting, Southern; D003106:Colon / Q000473:pathology; D004064:Digestive System / Q000473:pathology*; D004195:Disease Models, Animal; D005183:Failure to Thrive / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
D015513:Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1