Cul4B regulates neural progenitor cell growth

Helio C Liu,Yuzhi Chen,Grigori Enikolopov

doi:10.1186/1471-2202-13-112

Helio C Liu, Yuzhi Chen + Show 1 more

Open Access

https://doi.org/10.1186/1471-2202-13-112

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Abstract

BackgroundCullin 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.ResultsThere 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.ConclusionsThis 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.

Highlights

Cullin ubiquitin ligases are activated via the covalent modification of Cullins by the small ubiquitin-like protein nedd8 in a process called neddylation
Neddylation of Cullins may serve as a switch for a conformational change that leads to the activation of ubiquitination by Cullin-really interesting gene (RING) ubiquitin ligases (CRL)
Since Cul4B mutations are associated with X-linked intellectual disability (XLID), this study examined the functions of the endogenous Cul4B in Neural progenitor cell (NPC) and brain tissues

Summary

Introduction

Cullin ubiquitin ligases are activated via the covalent modification of Cullins by the small ubiquitin-like protein nedd in a process called neddylation. Ubiquitin ligases control the modification of proteins with ubiquitin by interacting with specific substrates. They play critical roles in neuronal functions and homeostasis. Mutations of the ubiquitin ligase Ube3A cause Angelman syndrome [1,2]. Ube3A regulates the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors [3]. Another example is that the ubiquitin ligase Parkin is mutated in early onset Parkinson’s disease [4].

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