Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

De novo truncations in ( ) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of causes neural dysfunction, we examined its function in and zebrafish. Overexpression of either or , the ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of P...

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Bibliographic Details
Published in:Science advances 2022-01, Vol.8 (3), p.eabl5613
Main Authors: Marcogliese, Paul C, Dutta, Debdeep, Ray, Shrestha Sinha, Dang, Nghi D P, Zuo, Zhongyuan, Wang, Yuchun, Lu, Di, Fazal, Fatima, Ravenscroft, Thomas A, Chung, Hyunglok, Kanca, Oguz, Wan, JiJun, Douine, Emilie D, Network, Undiagnosed Diseases, Pena, Loren D M, Yamamoto, Shinya, Nelson, Stanley F, Might, Matthew, Meyer, Kathrin C, Yeo, Nan Cher, Bellen, Hugo J
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Carrier Proteins - metabolism
Cellular Neuroscience
Child
Diseases and Disorders
Drosophila - genetics
Drosophila - metabolism
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Humans
Interferon Regulatory Factor-2 - metabolism
Nuclear Proteins - metabolism
Proto-Oncogene Proteins - genetics
SciAdv r-articles
Wnt Signaling Pathway
Wnt1 Protein - genetics
Wnt1 Protein - metabolism
Zebrafish - genetics
Zebrafish - metabolism
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Summary:De novo truncations in ( ) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of causes neural dysfunction, we examined its function in and zebrafish. Overexpression of either or , the ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased ( ) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of in zebrafish also causes neurological defects with an associated increase in transcription and downstream signaling. 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abl5613