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Nat Neurosci. 2014 Apr;17(4):506-12. doi: 10.1038/nn.3676. Epub 2014 Mar 9.

Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer.

Author information

1
1] Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Neurology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, UCSF, San Francisco, California, USA. [4].
2
1] Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, UCSF, San Francisco, California, USA. [3] Medical Scientist Training Program, UCSF, San Francisco, California, USA. [4].
3
Department of Neurology, UCSF, San Francisco, California, USA.
4
1] Department of Pediatrics, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, UCSF, San Francisco, California, USA.
5
Department of Pathology, UCSF, San Francisco, California, USA.
6
Department of Anatomy, UCSF, San Francisco, California, USA.

Erratum in

  • Nat Neurosci. 2014 Dec;17(12):1841.

Abstract

In colon cancer, mutation of the Wnt repressor APC (encoding adenomatous polyposis coli) leads to a state of aberrant and unrestricted high-activity signaling. However, the relevance of high Wnt tone in non-genetic human disease is unknown. Here we demonstrate that distinct functional states of Wnt activity determine oligodendrocyte precursor cell (OPC) differentiation and myelination. Mouse OPCs with genetic Wnt dysregulation (high tone) express multiple genes in common with colon cancer, including Lef1, Sp5, Ets2, Rnf43 and Dusp4. Surprisingly, we found that OPCs in lesions of hypoxic human neonatal white matter injury upregulated markers of high Wnt activity and lacked expression of APC. We also found that lack of Wnt repressor tone promoted permanent white matter injury after mild hypoxic insult. These findings suggest a state of pathological high-activity Wnt signaling in human disease tissues that lack predisposing genetic mutation.

Comment in

PMID:
24609463
PMCID:
PMC3975168
DOI:
10.1038/nn.3676
[Indexed for MEDLINE]
Free PMC Article
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