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The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation

Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm p...

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Autores principales: Xi, Xiao, Lu, Lu, Zhuge, Chun-Chun, Chen, Xuebing, Zhai, Yuanfen, Cheng, Jingjing, Mao, Haian, Yang, Chang-Ching, Tan, Bertrand Chin-Ming, Lee, Yi-Nan, Chien, Cheng-Ting, Ho, Margaret S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209662/
https://www.ncbi.nlm.nih.gov/pubmed/28051179
http://dx.doi.org/10.1038/srep39856
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author Xi, Xiao
Lu, Lu
Zhuge, Chun-Chun
Chen, Xuebing
Zhai, Yuanfen
Cheng, Jingjing
Mao, Haian
Yang, Chang-Ching
Tan, Bertrand Chin-Ming
Lee, Yi-Nan
Chien, Cheng-Ting
Ho, Margaret S.
author_facet Xi, Xiao
Lu, Lu
Zhuge, Chun-Chun
Chen, Xuebing
Zhai, Yuanfen
Cheng, Jingjing
Mao, Haian
Yang, Chang-Ching
Tan, Bertrand Chin-Ming
Lee, Yi-Nan
Chien, Cheng-Ting
Ho, Margaret S.
author_sort Xi, Xiao
collection PubMed
description Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). Gcm(R59L) interacts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. Gcm(R59L) proteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated.
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spelling pubmed-52096622017-01-04 The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation Xi, Xiao Lu, Lu Zhuge, Chun-Chun Chen, Xuebing Zhai, Yuanfen Cheng, Jingjing Mao, Haian Yang, Chang-Ching Tan, Bertrand Chin-Ming Lee, Yi-Nan Chien, Cheng-Ting Ho, Margaret S. Sci Rep Article Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). Gcm(R59L) interacts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. Gcm(R59L) proteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated. Nature Publishing Group 2017-01-04 /pmc/articles/PMC5209662/ /pubmed/28051179 http://dx.doi.org/10.1038/srep39856 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Xi, Xiao
Lu, Lu
Zhuge, Chun-Chun
Chen, Xuebing
Zhai, Yuanfen
Cheng, Jingjing
Mao, Haian
Yang, Chang-Ching
Tan, Bertrand Chin-Ming
Lee, Yi-Nan
Chien, Cheng-Ting
Ho, Margaret S.
The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation
title The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation
title_full The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation
title_fullStr The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation
title_full_unstemmed The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation
title_short The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation
title_sort hypoparathyroidism-associated mutation in drosophila gcm compromises protein stability and glial cell formation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209662/
https://www.ncbi.nlm.nih.gov/pubmed/28051179
http://dx.doi.org/10.1038/srep39856
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