title: Cul4B regulates neural progenitor cell growth.
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 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 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 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.
authors.affiliation: Department of Geriatrics, University of Arkansas for Medical Sciences, Slot 807, Little Rock, AR 72205, USA.
authors.forename: Helio C
authors.initials: HC
authors.lastname: Liu
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002552:Cerebral Ventricles / Q000166:cytology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D005434:Flow Cytometry; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D000075687:NEDD8 Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000502:physiology*; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C517832:CUL4B protein, human; D044842:Cullin Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D007381:Intermediate Filament Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D014452:Ubiquitins; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine