Loss of IRF2BPL Impairs Neuronal Maintenance Through Excess Wnt Signaling

Authors

Paul C Marcogliese
Debdeep Dutta
Shrestha Sinha Ray
Nghi D P Dang
Zhongyuan Zuo
Yuchun Wang
Di Lu
Fatima Fazal
Thomas A Ravenscroft
Hyunglok Chung
Oguz Kanca
JiJun Wan
Emilie D Douine
Undiagnosed Diseases Network
Loren D M Pena
Shinya Yamamoto
Stanley F Nelson
Matthew Might
Kathrin C Meyer
Nan Cher Yeo
Hugo J Bellen

Publication Date

1-21-2022

Journal

Science Advances

DOI

10.1126/sciadv.abl5613

PMID

35044823

PMCID

PMC8769555

PubMedCentral® Posted Date

1-19-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Carrier Proteins, Child, Drosophila, Drosophila Proteins, Humans, Interferon Regulatory Factor-2, Nuclear Proteins, Proto-Oncogene Proteins, Wnt Signaling Pathway, Wnt1 Protein, Zebrafish

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, 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.