Abstract
The study of physiologic functions of Wnt proteins has been complicated by the redundant nature of the families encoding the Wnt factors and their Frizzled receptors. Adenoviral expression of the secreted Wnt antagonist Dickkopf-1 (Dkk1) was used to achieve fully conditional inhibition of canonical Wnt signaling in adult mice. Systemic expression of Dkk1 resulted in rapid inhibition of Wnt target gene expression and of proliferation of the small intestine and colon, loss of proliferative crypts, and eventual inflammation and architectural degeneration. These studies indicate an essential requirement for extracellular Wnt signaling in the maintenance of adult small intestine and colon proliferation. The essential role of Wnt signaling in ongoing proliferation in the colon suggests potential clinical applications in mucosal repair for inflammatory bowel diseases and underscores the utility of adenoviral strategies for conditional ablation of gene function in adult organisms.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Adenoviridae / metabolism
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Cell Division / physiology
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Colon / cytology
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Colon / physiology*
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Epidermal Growth Factor / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Gene Expression Regulation
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Growth Substances / metabolism*
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Intercellular Signaling Peptides and Proteins
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Intestinal Mucosa / cytology
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Intestinal Mucosa / metabolism
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Intestine, Small / cytology
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Intestine, Small / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, SCID
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction / physiology
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TCF Transcription Factors
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Wnt Proteins
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Dkk1 protein, mouse
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Growth Substances
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Intercellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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Proteins
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Proto-Oncogene Proteins
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TCF Transcription Factors
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Tcf4 protein, mouse
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Transcription Factor 4
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Transcription Factors
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Wnt Proteins
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Epidermal Growth Factor