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

• Published in: Nature neuroscience Vol. 17; no. 4; pp. 506 - 512
• Main Authors: Fancy, Stephen P J, Harrington, Emily P, Baranzini, Sergio E, Silbereis, John C, Shiow, Lawrence R, Yuen, Tracy J, Huang, Eric J, Lomvardas, Stavros, Rowitch, David H
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2014; Nature Publishing Group
• Subjects: 631/378/2596/1705; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomarkers - metabolism; Biomedicine; Brain; Brain Injuries - metabolism; Brain Injuries - pathology; Brain Injuries - physiopathology; Cell cycle; Cell Differentiation; Colon cancer; Colonic Neoplasms - pathology; Colonic Neoplasms - physiopathology; Colorectal cancer; Diseases; Female; Gene Expression Regulation - physiology; Genetic Association Studies; Humans; Hypoxia; Hypoxia - metabolism; Infant, Newborn; Infant, Newborn, Diseases; Infants (Newborn); Injuries; Kinases; Leukoencephalopathies - metabolism; Mice; Mice, Transgenic; Mutation; Neurobiology; Neurological research; Neurosciences; Oligodendroglia - metabolism; Oligodendroglia - physiology; Physiological aspects; Proteins; Random Allocation; Spinal cord; Stem cells; Traumatic brain injury; Up-Regulation; Wnt proteins; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt Proteins - physiology; Wnt Signaling Pathway - genetics; Wnt Signaling Pathway - physiology; United States > US; San Francisco California; California
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3676

Much of what we know about the signal transduction machinery of the canonical Wnt pathway comes from studying the colon, where low- versus high-activity Wnt signaling states are known to distinguish normal colon epithelium turnover from colorectal cancer. Here, Fancy et al . demonstrate that a pathological Wnt activity state akin to that in colon cancer exists in oligodendrocyte precursor cells in human neonatal white matter injury, which leads to detrimental maturation arrest of these cells. These oligodendrocyte precursors in human newborn brain injury express multiple genes in common with colon cancer, demonstrating a pathological Wnt tone in non-genetic human disease. 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.