Axotomy-Induced Smad1 Activation Promotes Axonal Growth in Adult Sensory Neurons

Zou, Hongyan; Ho, Ching Lin; Wong, Karen; Tessier‐Lavigne, Marc

doi:10.1523/jneurosci.5397-08.2009

Cited by 150 publications

(154 citation statements)

References 29 publications

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“…1F) but reappears after a conditioning lesion (Fig. 1G) (15). The dynamic expression pattern of pSmad1 coincides with the changes of the intrinsic axon growth potential: embryonic and conditioned adult DRG neurons were able to extend much longer axons than adult naïve neurons in dissociated cultures ( Fig.…”

Section: Smad1 Is Developmentally Regulated In Drg Neurons and Governsmentioning

confidence: 53%

“…Previously, through gene expression profiling, we have demonstrated that Smad1 is induced after peripheral axotomy and that intraganglionic delivery of bone morphogenetic protein 2 or 4 (BMP2 or -4) activates Smad1 and enhances the axon growth potential of adult DRG neurons in cultures. In contrast, severing the central branches of DRGs fails to activate the Smad1 pathway, which correlates with the absence of regeneration after SCI (15).…”

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confidence: 99%

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Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Parikh

Hao

Hosseinkhani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

142

131

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Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adenoassociated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.intrinsic axon growth capacity | intrathecal viral vector delivery S pinal cord injury (SCI) disrupts long-projection axons, with devastating neurological outcomes, yet no effective clinical treatment exists. Neurons fail to regenerate axons because of a growth-inhibiting environment at the injury site (1-4) and because of an age-dependent decline in the intrinsic axon growth potential (5, 6). Nevertheless, blocking extracellular inhibitory molecules (7-10) or alleviating the intracellular negative regulators of axonal growth (5, 6, 11, 12) enables only limited axonal regeneration. Thus, additional molecular pathways that can rekindle innate growth capability must exist but remain unidentified (13).Dorsal root ganglion (DRG) neurons are a favored model system to study axonal regeneration. These neurons have an axon with two branches-a peripheral branch that innervates sensory organs and a central branch that relays information to the CNS. The central branches of adult DRG neurons in the spinal cord are refractory to regeneration unless their peripheral branches are severed first. This so-called "conditioning lesion" paradigm activates a transcription program that enhances the intrinsic axonal growth potential (14). Previously, through gene expression profiling, we have demonstrated that Smad1 is induced after peripheral axotomy and that intraganglionic delivery of bone morphogenetic protein 2 or 4 (BMP2 or -4) activates Smad1 and enhances the axon growth potential of adult DRG neurons in cultures. In contrast, severing the central branches of DRGs fails to activate the Smad1 pathway, which correlates with the absence of regeneration after SCI (15).These results suggested a possible involvement of Smad1 in regulating the growth state of DRG neurons. It is not known, however, whether Smad1 governs the axon growth program ...

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Section: Smad1 Is Developmentally Regulated In Drg Neurons and Governsmentioning

confidence: 53%

mentioning

confidence: 99%

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Parikh

Hao

Hosseinkhani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

142

131

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“…This idea is also supported by the strong reduction of SMAD1 expression in GSK3 S/A compared with wt DRG, as neuronal SMAD1 expression levels are regulated by GSK3 activity 8 . However, as axon regeneration was promoted in GSK3 S/A mice, these data demonstrate that elevation of SMAD1 expression above basal levels in wt animals is not required for the transformation of DRG neurons into a regenerative state, without excluding the possibility that basal SMAD1 levels are essential for axon growth 37 . Interestingly, despite the overall strong reduction of SMAD1 expression in GSK3 S/A mice, expression of this transcription factor was still increased after SNC in these animals, demonstrating GSK3 phosphorylation-independent upregulation.…”

Section: Discussionmentioning

confidence: 75%

Sustained GSK3 activity markedly facilitates nerve regeneration

et al. 2014

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Promotion of axonal growth of injured DRG neurons improves the functional recovery associated with peripheral nerve regeneration. Both isoforms of glycogen synthase kinase 3 (GSK3; a and b) are phosphorylated and inactivated via phosphatidylinositide 3-kinase (PI3K)/AKT signalling upon sciatic nerve crush (SNC). However, the role of GSK3 phosphorylation in this context is highly controversial. Here we use knock-in mice expressing GSK3 isoforms resistant to inhibitory PI3K/AKT phosphorylation, and unexpectedly find markedly accelerated axon growth of DRG neurons in culture and in vivo after SNC compared with controls. Moreover, this enhanced regeneration strikingly accelerates functional recovery after SNC. These effects are GSK3 activity dependent and associated with elevated MAP1B phosphorylation. Altogether, our data suggest that PI3K/AKT-mediated inhibitory phosphorylation of GSK3 limits the regenerative outcome after peripheral nerve injury. Therefore, suppression of this internal 'regenerative break' may potentially provide a new perspective for the clinical treatment of nerve injuries.

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“…Unilateral sciatic nerve crush was then performed as described previously (Zhong et al, 1999). Adult DRGs were collected and cultured as described previously (Zou et al, 2009). Images were taken using a Carl Zeiss LSM710NLO confocal microscope.…”

Section: Dorsal Root Crushmentioning

confidence: 99%

“…Images were taken using a Carl Zeiss LSM710NLO confocal microscope. Axon length was quantified as described previously (Zou et al, 2009). …”

Section: Dorsal Root Crushmentioning

confidence: 99%

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

O’Donovan¹,

Ma²,

Guo³

et al. 2014

J Cell Biol

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Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

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Axotomy-Induced Smad1 Activation Promotes Axonal Growth in Adult Sensory Neurons

Cited by 150 publications

References 29 publications

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Sustained GSK3 activity markedly facilitates nerve regeneration

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

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