title: The E3 ligase Cdh1-anaphase promoting complex operates upstream of the E3 ligase Smurf1 in the control of axon growth.
abstract: 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.
authors.affiliation: MPI of Experimental Medicine, Hermann Rein Strasse 3, 37075 Göttingen, Germany.
authors.forename: Madhuvanthi
authors.initials: M
authors.lastname: Kannan
authors.forename: Shih-Ju
authors.initials: SJ
authors.lastname: Lee
authors.forename: Nicola
authors.initials: N
authors.lastname: Schwedhelm-Domeyer
authors.forename: Judith
authors.initials: J
authors.lastname: Stegmüller
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: C066737:RHOA protein, human; D043743:Ubiquitin-Protein Ligase Complexes; C498342:SMURF1 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases; D020742:rhoA GTP-Binding Protein