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.
authors.affiliation: 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].
authors.forename: Stephen P J
authors.initials: SP
authors.lastname: Fancy
authors.affiliation: 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].
authors.forename: Emily P
authors.initials: EP
authors.lastname: Harrington
authors.affiliation: Department of Neurology, UCSF, San Francisco, California, USA.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.affiliation: 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.
authors.forename: John C
authors.initials: JC
authors.lastname: Silbereis
authors.affiliation: 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.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Shiow
authors.affiliation: 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.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Yuen
authors.affiliation: Department of Pathology, UCSF, San Francisco, California, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Department of Anatomy, UCSF, San Francisco, California, USA.
authors.forename: Stavros
authors.initials: S
authors.lastname: Lomvardas
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D056726:Genetic Association Studies; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D056784:Leukoencephalopathies / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000378:metabolism / Q000502:physiology*; D011897:Random Allocation; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D015415:Biomarkers; D051153:Wnt Proteins