Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Body Patterning / genetics
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Bromodeoxyuridine / metabolism
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Cell Proliferation
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Central Nervous System* / anatomy & histology
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Central Nervous System* / embryology
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Central Nervous System* / growth & development
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Embryo, Mammalian
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Fibrinolytic Agents / pharmacology
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Gene Expression / genetics
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Glycosylphosphatidylinositols / metabolism
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Heparin / pharmacology
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Histones / genetics
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Histones / metabolism
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In Situ Nick-End Labeling / methods
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Transgenic
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Mitosis / genetics*
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Protein Binding / drug effects
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Protein Binding / genetics
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Proteoglycans / metabolism*
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Stem Cells / classification
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Stem Cells / physiology
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Zinc Finger Protein Gli3
Substances
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Fibrinolytic Agents
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Gli3 protein, mouse
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Glycosylphosphatidylinositols
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Hedgehog Proteins
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Histones
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Kruppel-Like Transcription Factors
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Nerve Tissue Proteins
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Proteoglycans
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Shh protein, mouse
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Zinc Finger Protein Gli3
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Heparin
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Bromodeoxyuridine