PUBLICATION
A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal differentiation
- Authors
- Sobieszczuk, D.F., Poliakov, A., Xu, Q., and Wilkinson, D.G.
- ID
- ZDB-PUB-100311-1
- Date
- 2010
- Source
- Genes & Development 24(2): 206-218 (Journal)
- Registered Authors
- Wilkinson, David, Xu, Qiling
- Keywords
- Neurogenesis, ubiquitination, Plzf, Cul3 adaptor
- MeSH Terms
-
- Animals
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Cell Differentiation*
- Cell Line
- Chick Embryo
- Chickens
- Conserved Sequence
- Feedback, Physiological/physiology*
- Gene Expression Regulation, Developmental
- Gene Knockdown Techniques
- Humans
- Kruppel-Like Transcription Factors/antagonists & inhibitors
- Kruppel-Like Transcription Factors/metabolism
- Nerve Tissue Proteins/genetics
- Neurogenesis/physiology*
- Neurons/cytology*
- Neurons/physiology
- Protein Transport
- Ubiquitination
- Zebrafish/embryology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 20080956 Full text @ Genes & Dev.
Citation
Sobieszczuk, D.F., Poliakov, A., Xu, Q., and Wilkinson, D.G. (2010) A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal differentiation. Genes & Development. 24(2):206-218.
Abstract
Neuronal differentiation is regulated by proneural genes that promote neurogenesis and inhibitory mechanisms that maintain progenitors. This raises the question of how the up-regulation of proneural genes required to initiate neurogenesis occurs in the presence of such inhibition. We carried out loss and gain of gene function, an interaction screen for binding partners, and biochemical analyses to uncover the regulation, developmental role, and mechanism of action of a ubiquitination adaptor protein, Btbd6a (BTB domain containing 6a). We find that the proneural gene neurog1 up-regulates btbd6a, which in turn is required for up-regulation of neurog1. Btbd6a is an adaptor for the Cul3 ubiquitin ligase complex, and we find that it binds to the transcriptional repressor Plzf (promyelocytic leukemia zinc finger). Btbd6a promotes the relocation of Plzf from nucleus to cytoplasm and targets Plzf for ubiquitination and degradation. plzfa is expressed widely in the neural epithelium; when overexpressed, it inhibits neurogenesis, and this inhibition is reversed by btbd6a. The antagonism of endogenous plzfa by btbd6a is required for neurogenesis, since the block in neuronal differentiation caused by btbd6a knockdown is alleviated by plzfa knockdown. These findings reveal a feedback loop mediated by degradation of an inhibitor that is essential for progenitors to undergo the transition to neuronal differentiation.
Genes / Markers
Probes
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping