Rnd1 regulates axon extension by enhancing the microtubule destabilizing activity of SCG10.

Li, Yinghua; Ghavampour, Sharang; Bondallaz, Percy; Will, Lena; Grenningloh, Gabriele; Püschel, Andreas W.

doi:10.1074/jbc.a808126200

Cited by 11 publications

(14 citation statements)

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“…Other studies have also found that SCG10 levels are increased proximal to the site of traumatic injury in both the central and peripheral nervous systems (38)(39)(40). This SCG10 accumulation in the end bulbs of the proximal stump may be functionally important for axonal regeneration, because SCG10 within growth cones encourages the outgrowth of developing axons (23,(41)(42)(43). Of note, increased levels of SCG10 correlate closely with axon regeneration and sprouting after axon severing and ischemic brain injury (44)(45)(46).…”

Section: Discussionmentioning

confidence: 92%

“…During development SCG10 is required for axonal microtubules to be sufficiently dynamic to sustain axon outgrowth. When SCG10 levels are decreased, microtubule dynamism dwindles, and neurite outgrowth is restricted (41,42). Excessive microtubule stability also disrupts adult axons: Pharmacological microtubule stabilizers such as taxol induce axonal degeneration (47) and cause neuropathy in patients (48).…”

Section: Discussionmentioning

confidence: 99%

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SCG10 is a JNK target in the axonal degeneration pathway

Shin

Miller

Babetto

et al. 2012

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

164

216

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Axons actively self-destruct following genetic, mechanical, metabolic, and toxic insults, but the mechanism of axonal degeneration is poorly understood. The JNK pathway promotes axonal degeneration shortly after axonal injury, hours before irreversible axon fragmentation ensues. Inhibition of JNK activity during this period delays axonal degeneration, but critical JNK substrates that facilitate axon degeneration are unknown. Here we show that superior cervical ganglion 10 (SCG10), an axonal JNK substrate, is lost rapidly from mouse dorsal root ganglion axons following axotomy. SCG10 loss precedes axon fragmentation and occurs selectively in the axon segments distal to transection that are destined to degenerate. Rapid SCG10 loss after injury requires JNK activity. The JNK phosphorylation sites on SCG10 are required for its rapid degradation, suggesting that direct JNK phosphorylation targets SCG10 for degradation. We present a mechanism for the selective loss of SCG10 distal to the injury site. In healthy axons, SCG10 undergoes rapid JNK-dependent degradation and is replenished by fast axonal transport. Injury blocks axonal transport and the delivery of SCG10, leading to the selective loss of the labile SCG10 distal to the injury site. SCG10 loss is functionally important: Knocking down SCG10 accelerates axon fragmentation, whereas experimentally maintaining SCG10 after injury promotes mitochondrial movement and delays axonal degeneration. Taken together, these data support the model that SCG10 is an axonalmaintenance factor whose loss is permissive for execution of the injury-induced axonal degeneration program.A xon loss is a devastating consequence of a wide range of neurological diseases. A hallmark of hereditary neuropathies, glaucoma, and diabetic neuropathy, axon loss also is found early in the progression of debilitating neurodegenerative diseases such as Alzheimer's and Parkinson disease (1, 2). Although the great length of many axons is essential to their function, it also makes them vulnerable to mechanical trauma and to neurotoxins such as chemotherapeutics that interfere with axonal transport (3). Current therapies for axonal degeneration target either the systemic diseases that lead to axon loss or the pain that results from axon dysfunction (4). Therapies targeting the axon breakdown process itself are notably absent. Elucidating the mechanism of axonal degeneration may help to develop such therapies.Axonal degeneration is an actively regulated process that is blocked by the overexpression of the Wallerian degeneration slow (Wld s ) fusion protein or its enzymatically active component NMNAT (5-10). Regulated protein degradation promotes the degeneration of injured axons (11), potentially via the degradation of labile axonal-maintenance factors. Rapid postinjury loss of axonal-maintenance factors is a likely mechanism for promoting axon degeneration. NMNAT2 is the first identified axonal-maintenance factor that is degraded soon after injury. Its loss triggers axonal degeneration, and forced express...

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

SCG10 is a JNK target in the axonal degeneration pathway

Shin

Miller

Babetto

et al. 2012

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

164

216

View full text Add to dashboard Cite

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“…Unfortunately, there are to date no data arguing for or against this hypothesis. Nevertheless, the two families of MT destabilizing proteins in neurons, the stathmin and kinesin 13 families, have been studied in some detail, and although their function in axon guidance has not been defined, they do affect axon outgrowth and branching (Homma et al 2003; Suh et al 2004; Morii et al 2006; Tararuk et al 2006; Poulain and Sobel 2007; Li et al 2009). Interestingly, it appears that their destabilizing activity must be tightly regulated: too much and MT levels in the neurons fall, inhibiting outgrowth; too little and MTs grow to the tips of growth cones and form looped structures, also resulting in less outgrowth due to growth cone pausing.…”

Section: Microtubule-associated Proteins In Axon Guidancementioning

confidence: 99%

The Growth Cone Cytoskeleton in Axon Outgrowth and Guidance

Dent

Gupton

Gertler

2010

Cold Spring Harbor Perspectives in Biology

502

563

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Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. Over the past two decades, our knowledge of the many guidance cues, receptors, and downstream signaling cascades involved in neuronal outgrowth and guidance has increased dramatically. Less is known, however, about how those cascades of information converge and direct appropriate remodeling and interaction of cytoskeletal polymers, the ultimate effectors of movement and guidance. During development, much of the communication that occurs between environmental guidance cues and the cytoskeleton takes place at the growing tip of the axon, the neuronal growth cone. Several articles on this topic focus on the "input" to the growth cone, the myriad of receptor types, and their corresponding cognate ligands. Others investigate the signaling cascades initiated by receptors and propagated by second messenger pathways (i.e., kinases, phosphatases, GTPases). Ultimately, this plethora of information converges on proteins that associate directly with the actin and microtubule cytoskeletons. The role of these cytoskeletal-associated proteins, as well as the cytoskeleton itself in axon outgrowth and guidance, is the subject of this article.A s evidenced by other articles on this topic, our understanding of the cues, receptors, and signaling events underlying axon outgrowth and guidance has grown dramatically in recent years. Here, we focus on recent research involving cytoskeletal dynamics downstream of guidance receptor signaling that has begun to unravel the mechanisms underlying guided growth cone movement during development. We begin by covering how growth cone morphology changes during outgrowth and guidance. Since cytoskeletal dynamics underlie changes in growth cone morphology, we discuss where different cytoskeletal polymers reside in the growth cone and what forms of dynamic reorganization they undergo. We then present a description of selected actin-and microtubule-associated proteins that have been identified in developing neurons and discuss how they may function in axon outgrowth and guidance. Finally, we present a working model of how growth cones integrate multiple signaling

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“…The microtubule destabilizing factors, stathmin, superior cervical ganglia neural-specific 10 (SCG10), and SCG10-like protein (SCLIP) are highly expressed in nascent neurons, and represent a target of cellular signaling pathways to modulate microtubule dynamics in neurons. [173][174][175][176] Stathmin/ SCG10 family of proteins can destabilize microtubules and increase catastrophes by sequestering free tubulin and preventing its association with microtubule plus ends or by associating with tubulin on microtubule plus ends. 177,178 It appears an intricate balance of stathmin/SCG10 expression/activity is necessary for optimal neurite growth since neurons depleted of SCG10 or highly overexpressing it show reduced neurite growth.…”

Section: Building a Neurite-microtubulesmentioning

confidence: 99%

The cytoskeleton and neurite initiation

2013

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Neurons begin their life as simple spheres, but can ultimately assume an elaborate morphology with numerous, highly arborized dendrites, and long axons. This is achieved via an astounding developmental progression which is dependent upon regulated assembly and dynamics of the cellular cytoskeleton. As neurites emerge out of the soma, neurons break their spherical symmetry and begin to acquire the morphological features that define their structure and function. Neurons regulate their cytoskeleton to achieve changes in cell shape, velocity, and direction as they migrate, extend neurites, and polarize. Of particular importance, the organization and dynamics of actin and microtubules directs the migration and morphogenesis of neurons. This review focuses on the regulation of intrinsic properties of the actin and microtubule cytoskeletons and how specific cytoskeletal structures and dynamics are associated with the earliest phase of neuronal morphogenesis—neuritogenesis.

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Rnd1 regulates axon extension by enhancing the microtubule destabilizing activity of SCG10.

Cited by 11 publications

References 0 publications

SCG10 is a JNK target in the axonal degeneration pathway

SCG10 is a JNK target in the axonal degeneration pathway

The Growth Cone Cytoskeleton in Axon Outgrowth and Guidance

The cytoskeleton and neurite initiation

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