LIM Kinase1 Controls Synaptic Stability Downstream of the Type II BMP Receptor

Eaton, Benjamin A.; Davis, Graeme W.

doi:10.1016/j.neuron.2005.08.010

Cited by 161 publications

(202 citation statements)

References 65 publications

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“…2C). This lag time suggests that BMP signaling operates through a change on the transcriptional level, whereas an effect through LIM kinase-mediated local cytoskeletal stability seems less likely (18,19). Indeed, DM did not cause an acute collapse of growth cones; rather, a depletion of pSmad1 in nuclei was observed (Fig.…”

Section: Smad1 Is Developmentally Regulated In Drg Neurons and Governsmentioning

confidence: 94%

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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: 94%

“…Indeed, noncanonical BMP signaling pathways have been implicated in mediating local effects of BMPs-regulating actin dynamics in dendritogenesis (19), acute growth cone collapse (33), and synaptic stability (18).…”

Section: Sensory Axon Regeneration By Activation Of the Bmp Pathway In Amentioning

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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“…While the overwhelming evidence indicates that all Wit responses in motoneurons are mediated through Smads, it is also possible that some non-canonical pathways contribute to BMP neuronal signaling (Baines, 2004;Eaton and Davis, 2005;Sun et al, 2007). To the extent that these Smadindependent pathways operate through transcriptional regulation (Lee et al, 2007), their targets would also have been identified in this screen.…”

Section: Cg13565 Encodes a Putative Neuromodulator Regulated By Bmp Smentioning

confidence: 99%

Identification of downstream targets of the Bone Morphogenetic Protein pathway in the Drosophila nervous system

Kim

Marqués

2010

Developmental Dynamics

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Bone Morphogenetic Protein (BMP) signaling mediated by the receptor Wishful thinking (Wit) is essential for nervous system development in Drosophila. Mutants lacking wit function show defects in neuromuscular junction development and function, specification of neurosecretory phenotypes, and eclosion behavior that result in lethality. The ligand is Glass bottom boat, the Drosophila ortholog of mammalian BMP-7, which acts as a retrograde signal through the Wit receptor. In order to identify transcriptional targets of the BMP pathway in the Drosophila nervous system, we have analyzed the gene expression profile of wit mutant larval central nervous system. Genes differentially expressed identified by microarray analysis have been verified by quantitative PCR and studied by in situ hybridization. Among the genes thus identified, we find solute transporters, neuropeptides, mitochondrial proteins, and novel genes. In addition, several genes are regulated by wit in an isoform-specific manner that suggest regulation of alternative splicing by BMP signaling. Developmental Dynamics 239:2413-2425,

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“…Growth and differentiation of Drosophila neuromuscular junctions (NMJs) require the retrograde BMP signal, named Glass bottom boat (Gbb), which is secreted from postsynaptic muscles and activates presynaptic BMP signaling (5). Transduction of BMP signaling via phosphorylation and transcription in motorneurons stabilizes transient synaptic structure, leading to overall synaptic growth (6). Whereas it is well recognized that activity-induced up-regulation of retrograde signals potentiate synaptic properties, conceptually it is also possible that parallel retrograde signals playing negative roles in synaptic properties are down-regulated by synaptic activity.…”

mentioning

confidence: 99%

Activity-dependent retrograde laminin A signaling regulates synapse growth at Drosophila neuromuscular junctions

Tsai

Wang

Kao

et al. 2012

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

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Retrograde signals induced by synaptic activities are derived from postsynaptic cells to potentiate presynaptic properties, such as cytoskeletal dynamics, gene expression, and synaptic growth. However, it is not known whether activity-dependent retrograde signals can also depotentiate synaptic properties. Here we report that laminin A (LanA) functions as a retrograde signal to suppress synapse growth at Drosophila neuromuscular junctions (NMJs). The presynaptic integrin pathway consists of the integrin subunit βν and focal adhesion kinase 56 (Fak56), both of which are required to suppress crawling activity-dependent NMJ growth. LanA protein is localized in the synaptic cleft and only muscle-derived LanA is functional in modulating NMJ growth. The LanA level at NMJs is inversely correlated with NMJ size and regulated by larval crawling activity, synapse excitability, postsynaptic response, and anterograde Wnt/ Wingless signaling, all of which modulate NMJ growth through LanA and βν. Our data indicate that synaptic activities down-regulate levels of the retrograde signal LanA to promote NMJ growth.structural plasticity | BMP/Gbb | GluR | para | eag Sh

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LIM Kinase1 Controls Synaptic Stability Downstream of the Type II BMP Receptor

Cited by 161 publications

References 65 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

Identification of downstream targets of the Bone Morphogenetic Protein pathway in the Drosophila nervous system

Activity-dependent retrograde laminin A signaling regulates synapse growth at Drosophila neuromuscular junctions

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