Cul4B regulates neural progenitor cell growth
<p>Abstract</p> <p>Background</p> <p>Cullin ubiquitin ligases are activated via the covalent modification of Cullins by the small ubiquitin-like protein nedd8 in a process called neddylation. Genetic mutations of <it>cullin-4b (cul4b)</it> cause a prevalent...
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| Format: | Article |
| Language: | English |
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BMC
2012-09-01
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| Series: | BMC Neuroscience |
| Subjects: | |
| Online Access: | http://www.biomedcentral.com/1471-2202/13/112 |
| _version_ | 1831519639427874816 |
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| author | Liu Helio C Enikolopov Grigori Chen Yuzhi |
| author_facet | Liu Helio C Enikolopov Grigori Chen Yuzhi |
| author_sort | Liu Helio C |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Cullin ubiquitin ligases are activated via the covalent modification of Cullins by the small ubiquitin-like protein nedd8 in a process called neddylation. Genetic mutations of <it>cullin-4b (cul4b)</it> cause a prevalent type of X-linked intellectual disability (XLID) in males, but the physiological function of Cul4B in neuronal cells remains unclear.</p> <p>Results</p> <p>There are three major isoforms of Cul4B (1, 2, and 3) in human and rodent tissues. By examining the endogenous Cul4B isoforms in the brain, this study demonstrates that Cul4B-1 and Cul4B-2 isoforms are unneddylated and more abundant in the brain whereas the lesser species Cul4B-3 that misses the N-terminus present in the other two isoforms is neddylated. The data suggest that the N-terminus of Cul4B inhibits neddylation in the larger isoforms. Immunostaining of human NT-2 cells also shows that most Cul4B is unneddylated, especially when it is localized in the process in G0-synchronized cells. This study demonstrates that Cul4B accumulates during mitosis and downregulation of Cul4B arrests NPCs and NT-2 cells in the G2/M phase of the cell cycle. In both human and rodent brain tissues, Cul4B-positive cells accumulate β-catenin in the dentate subgranular zone and the subventricular zone. These Cul4B-positive cells also co-express the MPM-2 mitotic epitope, suggesting that Cul4B is also necessary for mitosis progression <it>in vivo</it>.</p> <p>Conclusions</p> <p>This study provides first evidence that unneddylated Cul4B isoforms exist in the brain and are necessary for mitosis progression in NPCs. The data suggest that unneddylated Cul4B isoforms specifically inhibits β-catenin degradation during mitosis. Furthermore, unneddylated Cul4B may play a role in addition to cell cycle since it is exclusively localized to the processes in starved NT-2 cells. Further analyses of the different isoforms of Cul4B will help understand the cognitive deficits in Cul4B-linked XLID and give insights into drug and biomarker discoveries.</p> |
| first_indexed | 2024-12-13T17:17:57Z |
| format | Article |
| id | doaj.art-5db0cd9acd354a198a7ef434bfed55e9 |
| institution | Directory Open Access Journal |
| issn | 1471-2202 |
| language | English |
| last_indexed | 2024-12-13T17:17:57Z |
| publishDate | 2012-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neuroscience |
| spelling | doaj.art-5db0cd9acd354a198a7ef434bfed55e92022-12-21T23:37:22ZengBMCBMC Neuroscience1471-22022012-09-0113111210.1186/1471-2202-13-112Cul4B regulates neural progenitor cell growthLiu Helio CEnikolopov GrigoriChen Yuzhi<p>Abstract</p> <p>Background</p> <p>Cullin ubiquitin ligases are activated via the covalent modification of Cullins by the small ubiquitin-like protein nedd8 in a process called neddylation. Genetic mutations of <it>cullin-4b (cul4b)</it> cause a prevalent type of X-linked intellectual disability (XLID) in males, but the physiological function of Cul4B in neuronal cells remains unclear.</p> <p>Results</p> <p>There are three major isoforms of Cul4B (1, 2, and 3) in human and rodent tissues. By examining the endogenous Cul4B isoforms in the brain, this study demonstrates that Cul4B-1 and Cul4B-2 isoforms are unneddylated and more abundant in the brain whereas the lesser species Cul4B-3 that misses the N-terminus present in the other two isoforms is neddylated. The data suggest that the N-terminus of Cul4B inhibits neddylation in the larger isoforms. Immunostaining of human NT-2 cells also shows that most Cul4B is unneddylated, especially when it is localized in the process in G0-synchronized cells. This study demonstrates that Cul4B accumulates during mitosis and downregulation of Cul4B arrests NPCs and NT-2 cells in the G2/M phase of the cell cycle. In both human and rodent brain tissues, Cul4B-positive cells accumulate β-catenin in the dentate subgranular zone and the subventricular zone. These Cul4B-positive cells also co-express the MPM-2 mitotic epitope, suggesting that Cul4B is also necessary for mitosis progression <it>in vivo</it>.</p> <p>Conclusions</p> <p>This study provides first evidence that unneddylated Cul4B isoforms exist in the brain and are necessary for mitosis progression in NPCs. The data suggest that unneddylated Cul4B isoforms specifically inhibits β-catenin degradation during mitosis. Furthermore, unneddylated Cul4B may play a role in addition to cell cycle since it is exclusively localized to the processes in starved NT-2 cells. Further analyses of the different isoforms of Cul4B will help understand the cognitive deficits in Cul4B-linked XLID and give insights into drug and biomarker discoveries.</p>http://www.biomedcentral.com/1471-2202/13/112CullinNeurogenesisUbiquitinationNeddylationMental retardationβ-catenin |
| spellingShingle | Liu Helio C Enikolopov Grigori Chen Yuzhi Cul4B regulates neural progenitor cell growth BMC Neuroscience Cullin Neurogenesis Ubiquitination Neddylation Mental retardation β-catenin |
| title | Cul4B regulates neural progenitor cell growth |
| title_full | Cul4B regulates neural progenitor cell growth |
| title_fullStr | Cul4B regulates neural progenitor cell growth |
| title_full_unstemmed | Cul4B regulates neural progenitor cell growth |
| title_short | Cul4B regulates neural progenitor cell growth |
| title_sort | cul4b regulates neural progenitor cell growth |
| topic | Cullin Neurogenesis Ubiquitination Neddylation Mental retardation β-catenin |
| url | http://www.biomedcentral.com/1471-2202/13/112 |
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