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Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling
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,...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769555/ https://www.ncbi.nlm.nih.gov/pubmed/35044823 http://dx.doi.org/10.1126/sciadv.abl5613 |
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author | 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. |
author_facet | 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. |
author_sort | Marcogliese, Paul C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8769555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-87695552022-02-01 Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling 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. Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2022-01-19 /pmc/articles/PMC8769555/ /pubmed/35044823 http://dx.doi.org/10.1126/sciadv.abl5613 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences 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. Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling |
title | Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling |
title_full | Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling |
title_fullStr | Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling |
title_full_unstemmed | Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling |
title_short | Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling |
title_sort | loss of irf2bpl impairs neuronal maintenance through excess wnt signaling |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769555/ https://www.ncbi.nlm.nih.gov/pubmed/35044823 http://dx.doi.org/10.1126/sciadv.abl5613 |
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