Inhibitor of DNA binding 2 promotes sensory axonal growth after SCI

Shields, Lisa B. E.; Zheng, Yiyan; Hu, Xiaoling; Hill, Rachel L.; Howard, Russell M.; Gu, Zhifeng; Burke, Darlene A.; Whittemore, Scott R.; Xu, Xiao–Ming; Shields, Christopher B.

doi:10.1016/j.expneurol.2011.05.013

Cited by 33 publications

(30 citation statements)

References 31 publications

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“…As a further line of evidence for this pathway, the Cdh1 substrate Id2 was stabilized in the nuclei of RelA CNSKO neuronal cultures. Increases in the steady-state levels of Id2, either as a result of the overexpression of a ubiquitylationresistant D-box mutant or of Cdh1 knockdown, have been reported to stimulate the axonal outgrowth of immature neurons and to enhance the regeneration of dorsal root ganglion neurons after SCI (Lasorella et al, 2006;Yu et al, 2011). As for Cdh1, its pro-regenerative effects might only partly depend on the processes of ubiquitylation and proteasomal degradation that are essential for cell-cycle control (e.g.…”

Section: Discussionmentioning

confidence: 99%

NF-κB determines axonal re- and degeneration by cell-specific balance of RelA and p50 subunits in the adult CNS

Haenold

Weih

Herrmann

et al. 2014

Journal of Cell Science

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NF-kB is dually involved in neurogenesis and brain pathology. Here, we addressed its role in adult axoneogenesis by generating mutations of RelA (p65) and p50 (also known as NFKB1) heterodimers of canonical NF-kB. In addition to RelA activation in astrocytes, optic nerve axonotmesis caused a hitherto unrecognized induction of RelA in growth-inhibitory oligodendrocytes. Intraretinally, RelA was induced in severed retinal ganglion cells and was also expressed in bystander Mü ller glia. Cell-type-specific deletion of transactivating RelA in neurons and/or macroglia stimulated axonal regeneration in a distinct and synergistic pattern. By contrast, deletion of the p50 suppressor subunit promoted spontaneous and post-injury Wallerian degeneration. Growth effects mediated by RelA deletion paralleled a downregulation of growth-inhibitory Cdh1 (officially known as FZR1) and upregulation of the endogenous Cdh1 suppressor EMI1 (officially known as FBXO5). Pro-degenerative loss of p50, however, stabilized retinal Cdh1. In vitro, RelA deletion elicited opposing pro-regenerative shifts in active nuclear and inactive cytoplasmic moieties of Cdh1 and Id2. The involvement of NF-kB and cell-cycle regulators such as Cdh1 in regenerative processes of non-replicative neurons suggests novel mechanisms by which molecular reprogramming might be executed to stimulate adult axoneogenesis and treat central nervous system (CNS) axonopathies.

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Section: Discussionmentioning

confidence: 99%

NF-κB determines axonal re- and degeneration by cell-specific balance of RelA and p50 subunits in the adult CNS

Haenold

Weih

Herrmann

et al. 2014

Journal of Cell Science

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“…That the Cdh1-APC pathway of axon growth suppression does play an essential role in the failure of CNS regeneration has been demonstrated in a spinal cord injury study, in which the degradation-resistant Cdh1-APC substrate Id2 allows axons to grow past the injury site (Yu et al, 2011). Thus, it will be important to determine the regenerative role of Smurf1 and Cdh1 inhibition in CNS injury models.…”

Section: Research Articlementioning

confidence: 99%

The E3 ligase Cdh1-anaphase promoting complex operates upstream of the E3 ligase Smurf1 in the control of axon growth

et al. 2012

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SUMMARYAxon 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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“…These results suggest that Cdh1-APC-induced degradation of Id2 induces the expression of a program of axon growth inhibitory signals. Like SnoN, Id2 may also promote the regeneration of axons following injury (Yu et al 2011). Expression of the D-box mutant Id2 using adenovirus-based Figure 4.…”

Section: Regulation Of Neuronal Morphogenesis By Cdh1-apc and Cdc20-apcmentioning

confidence: 99%

“…gene delivery in DRG neurons stimulates axon growth in the lesioned dorsal ascending axons following dorsal spinal cord hemisection (Yu et al 2011), suggesting that inhibiting Cdh1-APC-mediated degradation of Id2 facilitates axon regeneration after spinal cord injury. By inducing the degradation of SnoN and Id2, Cdh1-APC therefore acts as a pivotal cell-intrinsic regulator of axon growth by controlling the responsiveness of axons to extrinsic cues and intracellular signaling proteins.…”

Section: Regulation Of Neuronal Morphogenesis By Cdh1-apc and Cdc20-apcmentioning

confidence: 99%

A decade of the anaphase-promoting complex in the nervous system

Huang

Bonni

2016

Genes Dev.

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Control of protein abundance by the ubiquitin-proteasome system is essential for normal brain development and function. Just over a decade ago, the first post-mitotic function of the anaphase-promoting complex, a major cell cycle-regulated E3 ubiquitin ligase, was discovered in the control of axon growth and patterning in the mammalian brain. Since then, a large number of studies have identified additional novel roles for the anaphase-promoting complex in diverse aspects of neuronal connectivity and plasticity in the developing and mature nervous system. In this review, we discuss the functions and mechanisms of the anaphase-promoting complex in neurogenesis, glial differentiation and migration, neuronal survival and metabolism, neuronal morphogenesis, synapse formation and plasticity, and learning and memory. We also provide a perspective on future investigations of the anaphase-promoting complex in neurobiology.Protein degradation regulates diverse biological processes in the developing and mature nervous system. Spatial and temporal control of protein turnover and abundance influences distinct stages of neural development and function from neurogenesis and neuronal morphogenesis to synapse formation and pruning to plasticity and learning (Hegde and Upadhya 2007;Yi and Ehlers 2007;Segref and Hoppe 2009;Yamada et al. 2013). Protein degradation by the proteasome requires ubiquitination, which is mediated by the sequential action of an E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase (Hershko and Ciechanover 1992;Scheffner et al. 1995;Ciechanover 2005;Hershko 2005;Weissman et al.

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Inhibitor of DNA binding 2 promotes sensory axonal growth after SCI

Cited by 33 publications

References 31 publications

NF-κB determines axonal re- and degeneration by cell-specific balance of RelA and p50 subunits in the adult CNS

NF-κB determines axonal re- and degeneration by cell-specific balance of RelA and p50 subunits in the adult CNS

The E3 ligase Cdh1-anaphase promoting complex operates upstream of the E3 ligase Smurf1 in the control of axon growth

A decade of the anaphase-promoting complex in the nervous system

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