Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS

Hyun Kyoung Lee; Lesley S Chaboub; Wenyi Zhu; Daniel Zollinger; Matthew N Rasband; Stephen P J Fancy; Benjamin Deneen

doi:10.1016/j.neuron.2015.02.024

Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS

Neuron. 2015 Mar 18;85(6):1227-43. doi: 10.1016/j.neuron.2015.02.024. Epub 2015 Mar 5.

Authors

Hyun Kyoung Lee¹, Lesley S Chaboub², Wenyi Zhu³, Daniel Zollinger⁴, Matthew N Rasband⁴, Stephen P J Fancy⁵, Benjamin Deneen⁶

Affiliations

¹ Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
² 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.
³ 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.
⁴ Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
⁵ Departments of Pediatrics and Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California 94143, USA.
⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Mice
Microfilament Proteins / genetics
Microfilament Proteins / metabolism*
Myelin Sheath / metabolism
Oligodendroglia / cytology*
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
Regeneration / physiology
Signal Transduction / physiology
Spinal Cord / metabolism*
Spinal Cord / pathology
White Matter / injuries
Wnt Proteins / metabolism*
Wnt Signaling Pathway*
rho GTP-Binding Proteins / genetics
rho GTP-Binding Proteins / metabolism*

Substances

Daam2 protein, mouse
Microfilament Proteins
Wnt Proteins
Phosphotransferases (Alcohol Group Acceptor)
rho GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding