Cul4B regulates neural progenitor cell growth

Liu, H. C., Enikolopov, G., Chen, Y. Z. (September 2012) Cul4B regulates neural progenitor cell growth. BMC Neuroscience, 13. p. 13. ISSN 1471-2202

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URL: http://www.ncbi.nlm.nih.gov/pubmed/22992378

DOI: 10.1186/1471-2202-13-112

Abstract

Background: 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 cullin-4b (cul4b) cause a prevalent type of X-linked intellectual disability (XLID) in males, but the physiological function of Cul4B in neuronal cells remains unclear. Results: 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 beta-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 in vivo. Conclusions: 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 beta-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.

Item Type:	Paper
Uncontrolled Keywords:	Cullin Neurogenesis Ubiquitination Neddylation Mental retardation beta-catenin LINKED MENTAL-RETARDATION RING UBIQUITIN LIGASES BETA-CATENIN ANGELMAN SYNDROME NEDD8 CONJUGATION DNA-DAMAGE DEGRADATION MUTATIONS CYCLE ACTIVATION
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function neurobiology organs, tissues, organelles, cell types and functions > cell types and functions > cell types > progenitor cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > progenitor cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > progenitor cell
CSHL Authors:	Enikolopov, Grigori N.
Communities:	CSHL labs > Enikopolov lab
Depositing User:	Matt Covey
Date:	September 2012
Date Deposited:	20 Dec 2013 16:33
Last Modified:	20 Dec 2013 16:33
PMCID:	PMC3506489
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/29124

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