Journal
NATURE NEUROSCIENCE
Volume 12, Issue 4, Pages 409-417Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2287
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Funding
- US National Institutes of Health
- Dana Farber Cancer Institute Mahoney Center for Neuro-Oncology
- Musella Foundation
- Quan Fellowship
- Children's Hospital Mental Retardation and Developmental Disabilities Research Center
- Harvard NeuroDiscovery Center
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Sonic Hedgehog (Shh) has dual roles in vertebrate development, promoting progenitor cell proliferation and inducing tissue patterning. We found that the mitogenic and patterning functions of Shh can be uncoupled from one another. Using a genetic approach to selectively inhibit Shh-proteoglycan interactions in a mouse model, we found that binding of Shh to proteoglycans was required for proliferation of neural stem/precursor cells, but not for tissue patterning. Shh-proteoglycan interactions regulated both spatial and temporal features of Shh signaling. Proteoglycans localized Shh to specialized mitogenic niches and also acted at the single-cell level to regulate the duration of Shh signaling, thereby promoting a gene expression program that is important for cell division. Because activation of the Shh pathway is a feature of diverse human cancers, selective stimulation of proliferation by Shh-proteoglycan interactions may also figure prominently in neoplastic growth.
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