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DEVELOPMENT AND DISEASE |
1 Skirball Institute of Biomolecular Medicine, Developmental Genetics Program and Department of Cell Biology, NYU School of Medicine, 540 First Avenue, New York, NY 10016, USA
2 Department of Neurosurgery, NYU School of Medicine, 540 First Avenue, New York, NY 10016, USA
* Present address: Institute for Developmental Biology, CNRS, Marseille, France
Author for correspondence (e-mail: ria{at}saturn.med.nyu.edu)
Accepted September 24, 2001
The mechanisms that regulate the growth of the brain remain unclear. We show that Sonic hedgehog (Shh) is expressed in a layer-specific manner in the perinatal mouse neocortex and tectum, whereas the Gli genes, which are targets and mediators of SHH signaling, are expressed in proliferative zones. In vitro and in vivo assays show that SHH is a mitogen for neocortical and tectal precursors and that it modulates cell proliferation in the dorsal brain. Together with its role in the cerebellum, our findings indicate that SHH signaling unexpectedly controls the development of the three major dorsal brain structures. We also show that a variety of primary human brain tumors and tumor lines consistently express the GLI genes and that cyclopamine, a SHH signaling inhibitor, inhibits the proliferation of tumor cells. Using the in vivo tadpole assay system, we further show that misexpression of GLI1 induces CNS hyperproliferation that depends on the activation of endogenous Gli1 function. SHH-GLI signaling thus modulates normal dorsal brain growth by controlling precursor proliferation, an evolutionarily important and plastic process that is deregulated in brain tumors.
Key words: Mouse, Xenopus, GLI, SHH, Brain, Tumor, Neocortex, Tectum, Growth, CNS
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