title: Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS.
abstract: Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS; however, contributions of proximal regulators of the Wnt receptor complex to these processes remain undefined. To identify components of the Wnt pathway that regulate these processes, we applied a multifaceted discovery platform and found that Daam2-PIP5K comprise a novel pathway regulating Wnt signaling and myelination. Using dorsal patterning of the chick spinal cord we found that Daam2 promotes Wnt signaling and receptor complex formation through PIP5K-PIP2. Analysis of Daam2 function in oligodendrocytes (OLs) revealed that it suppresses OL differentiation during development, after white matter injury (WMI), and is expressed in human white matter lesions. These findings suggest a pharmacological strategy to inhibit Daam2-PIP5K function, application of which stimulates remyelination after WMI. Put together, our studies integrate information from multiple systems to identify a novel regulatory pathway for Wnt signaling and potential therapeutic target for WMI.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Hyun Kyoung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Lesley S
authors.initials: LS
authors.lastname: Chaboub
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zollinger
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Rasband
authors.affiliation: Departments of Pediatrics and Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California 94143, USA.
authors.forename: Stephen P J
authors.initials: SP
authors.lastname: Fancy
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. Electronic address: deneen@bcm.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Deneen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D066127:White Matter / Q000293:injuries; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C500366:Daam2 protein, mouse; D008840:Microfilament Proteins; D051153:Wnt Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D020741:rho GTP-Binding Proteins