Abstract
Graded Hedgehog (Hh) signaling governs the balance of Gli transcriptional activators and repressors to specify diverse ventral cell fates in the spinal cord. It remains unclear how distinct intracellular Gli activity is generated. Here, we demonstrate that Sufu acts universally as a negative regulator of Hh signaling, whereas Kif7 inhibits Gli activity in cooperation with, and independent of, Sufu. Together, they deter naïve precursors from acquiring increasingly ventral identity. We show that Kif7 is also required to establish high intracellular Gli activity by antagonizing the Sufu-inhibition of Gli2. Strikingly, by abolishing the negative regulatory action of Sufu, diverse ventral cell fates can be specified in the absence of extracellular Hh signaling. These data suggest that Sufu is the primary regulator of graded Hh signaling and establish that the antagonistic and cooperative actions of Kif7 and Sufu are responsible for setting up distinct Gli activity in ventral cell fate specification.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Blotting, Western
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Cell Differentiation / physiology*
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Fluorescent Antibody Technique
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Hedgehog Proteins / metabolism*
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In Situ Hybridization
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Kinesins / genetics
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Kinesins / metabolism*
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Kruppel-Like Transcription Factors / metabolism*
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Mice
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Mice, Knockout
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Microscopy, Confocal
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction / physiology*
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Spinal Cord / cytology
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Spinal Cord / embryology*
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Zinc Finger Protein GLI1
Substances
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Gli1 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Repressor Proteins
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Sufu protein, mouse
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Zinc Finger Protein GLI1
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Kif7 protein, mouse
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Kinesins
Grants and funding
This work was supported by a University of Toronto Open Fellowship to Kelvin Law and funded by the Canadian Cancer Society Research Institute (2010-700320 and 2011-700774) to Chi-chung Hui (
http://www.cancer.ca/Research.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.