Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

Sci Adv. 2022 Jan 21;8(3):eabl5613. doi: 10.1126/sciadv.abl5613. Epub 2022 Jan 19.


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, represses Wnt transcription 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 signaling 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 with an associated increase in wnt1 transcription and downstream signaling. WNT1 is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Last, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt transcription and signaling.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Child
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Humans
  • Interferon Regulatory Factor-2 / metabolism
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Wnt Signaling Pathway
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism
  • Zebrafish / genetics
  • Zebrafish / metabolism


  • Carrier Proteins
  • Drosophila Proteins
  • IRF2BPL protein, human
  • Interferon Regulatory Factor-2
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Wnt1 Protein