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Expression of Human GLI in Mice Results in Failure to Thrive, Early Death, and Patchy Hirschsprung-like Gastrointestinal Dilatation

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Abstract

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-deteimining 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.

Materials and 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.

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Acknowledgments

We thank Dr. M. DalCanto for performing the CNS histologic evaluation of the transgenic mice and Dr. P. Chou for histologic evaluation of GI tract walls. This work was aided by grants 93-32 and 94-51 from the American Cancer Society, Illinois Division, Inc. and was supported in part by Public Health Service grant CA64395 from the National Cancer Institute and HD28992 from the National Institute of Child Health and Human Development.

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Authors and Affiliations

  1. Department of Pediatrics and Children’s Memorial Institute for Education and Research, Northwestern University Medical School, 2300 Children’s Plaza, MC 204, Chicago, Illinois, 60614, USA

    Jian Tao Yang, Cheng Zheng Liu, Elisabeth H. Villavicencio, Joon Won Yoon, David Walterhouse &  Philip M. Iannaccone

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  1. Jian Tao Yang
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  2. Cheng Zheng Liu
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  3. Elisabeth H. Villavicencio
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Correspondence to Philip M. Iannaccone.

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Yang, J.T., Liu, C.Z., Villavicencio, E.H. et al. Expression of Human GLI in Mice Results in Failure to Thrive, Early Death, and Patchy Hirschsprung-like Gastrointestinal Dilatation. Mol Med 3, 826–835 (1997). https://doi.org/10.1007/BF03401719

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