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Induction of Medulloblastomas in Mice by Sonic Hedgehog, Independent of Gli1^{1 ,,2}

Skirball Institute of Biomolecular Medicine [H. L. W., R. B., M. S. H., E. A., W. S. L., D. S., A. L. J., D. H. T.], Howard Hughes Medical Institute [A. L. J.], and Departments of Neurosurgery [H. L. W., R. B., J. R., E. A., W. S. L., D. Z.], Pathology [D. Z., D. H. T.], Cell Biology [A. L. J.], Physiology/Neuroscience [A. L. J.], and Radiology [D. H. T.], New York University School of Medicine, New York, New York 10016

The Sonic hedgehog (Shh) signaling pathway plays a critical role in normal cerebellar development and has been implicated in medulloblastomas, common malignant childhood tumors of the cerebellum. To test whether Shh mis-expression is sufficient for medulloblastoma formation, we used ultrasound biomicroscopy-guided in utero injection of a Shh-expressing retrovirus into the cerebellum of 13.5-day mouse embryos to show that direct activation of the Shh pathway can lead to tumor formation. Significantly, medulloblastomas were observed in 76% of the mice infected with Shh-expressing retrovirus. Furthermore, contrary to recent suggestions that the Shh transcriptional target Gli1 plays a critical role in Shh-induced tumorigenesis, we found that medulloblastomas form in Gli1 null mutant mice. We have developed an efficient mouse model of medulloblastoma and shown that Gli1 is not required for tumorigenesis when Shh signaling is activated upstream in the pathway.

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