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

Stephen P.J. Fancy; Emily P. Harrington; Sergio E. Baranzini; John C. Silbereis; Lawrence R. Shiow; Tracy J. Yuen; Eric J. Huang; Stavros Lomvardas; David H. Rowitch

doi:10.1038/nn.3676

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

Stephen P.J. Fancy
, Emily P. Harrington
, Sergio E. Baranzini
, John C. Silbereis
, Lawrence R. Shiow
, Tracy J. Yuen
, Eric J. Huang
, Stavros Lomvardas
, David H. Rowitch

Research output: Contribution to journal › Article › peer-review

103 Scopus citations

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.

Original language	English
Pages (from-to)	506-512
Number of pages	7
Journal	Nature neuroscience
Volume	17
Issue number	4
DOIs	https://doi.org/10.1038/nn.3676
State	Published - Apr 2014

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title = "Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer",

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.",

author = "Fancy, \{Stephen P.J.\} and Harrington, \{Emily P.\} and Baranzini, \{Sergio E.\} and Silbereis, \{John C.\} and Shiow, \{Lawrence R.\} and Yuen, \{Tracy J.\} and Huang, \{Eric J.\} and Stavros Lomvardas and Rowitch, \{David H.\}",

year = "2014",

month = apr,

doi = "10.1038/nn.3676",

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AU - Fancy, Stephen P.J.

AU - Harrington, Emily P.

AU - Baranzini, Sergio E.

AU - Silbereis, John C.

AU - Shiow, Lawrence R.

AU - Yuen, Tracy J.

AU - Huang, Eric J.

AU - Lomvardas, Stavros

AU - Rowitch, David H.

PY - 2014/4

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N2 - 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.

AB - 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.

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DO - 10.1038/nn.3676

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JO - Nature neuroscience

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

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