Journal
DEVELOPMENT
Volume 139, Issue 19, Pages 3600-3612Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.081786
Keywords
Cdh1-APC; Smurf1; Axon growth; Myelin; Ubiquitylation; Mouse; Rat
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Funding
- Max Planck Society
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
- GGNB (Gottingen Graduate School for Neurosciences and Molecular Biosciences) Excellence Stipend of the University of Gottingen
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Axon growth is an essential event during brain development and is extremely limited due to extrinsic and intrinsic inhibition in the adult brain. The E3 ubiquitin ligase Cdh1-anaphase promoting complex (APC) has emerged as an important intrinsic suppressor of axon growth. In this study, we identify in rodents the E3 ligase Smurf1 as a novel substrate of Cdh1-APC and that Cdh1 targets Smurf1 for degradation in a destruction box-dependent manner. We find that Smurf1 acts downstream of Cdh1-APC in axon growth and that the turnover of RhoA by Smurf1 is important in this process. In addition, we demonstrate that acute knockdown of Smurf1 in vivo in the developing cerebellar cortex results in impaired axonal growth and migration. Finally, we show that a stabilized form of Smurf1 overrides the inhibition of axon growth by myelin. Taken together, we uncovered a Cdh1-APC/Smurf1/RhoA pathway that mediates axonal growth suppression in the developing mammalian brain.
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