Author(s): Paul C. Marcogliese, Baylor College of Medicine; Debdeep Dutta, Baylor College of Medicine; Shrestha Sinha-Ray, The Research Institute at Nationwide Children’s Hospital; Shinya Yamamoto, Baylor College of Medicine; Kathrin C Meyer, The Research Institute at Nationwide Children’s Hospital; Nan Cher Yeo, University of Alabama, Birmingham; Hugo J. Bellen, Baylor College of Medicine //

ABSTRACT: De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, impairs Wnt signaling in flies. In contrast, neuronal depletion of Pits leads to increased Wingless (Wg) levels in the brain and is associated with axonal loss whereas inhibition of Wg is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of irf2bpl in zebrafish also causes neurological defects and increased Wnt signaling. WNT1 is also upregulated in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Finally, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt signaling.

Source of Funding: This work was primarily supported by the Stand by Eli foundation (www.standbyeli.org) via The Giving Back Fund (www.givingback.org). Research was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number P50HD103555 for use of the Neurovisualization core facilities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Proteomics was performed by S. Y. Jung, A. Jain in the BCM Pathway Discovery Proteomics Core (CPRIT RP120092 and P30CA125123). This work was also supported by NIH grant U01 HG007703 and NIH-supplement (5U01G007530-06). P.C.M. is supported by CIHR (MFE-164712). H.J.B. is an investigator of the Howard Hughes Medical Institute (HHMI) and thanks HHMI for support.