Suppression of Rho-kinase activity promotes axonal growth on inhibitory CNS substrates

Borisoff, Jaimie; Chan, Carmen C.M.; Hiebert, Gordon W.; Oschipok, Loren W.; Robertson, George S.; Zamboni, Robert; Steeves, John D.; Tetzlaff, Wolfram

doi:10.1016/s1044-7431(02)00032-5

Cited by 195 publications

(145 citation statements)

References 50 publications

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“…Accordingly, human hemizygosity of LIM-domain-containing protein kinase (LIMK), which is activated by p21-activated kinase (PAK), an effector of Rac GTPase, has been associated with MR (23). On the other hand, Rho activation has been shown to cause neurite retraction (39,40) by means of formation of stress fibers in the growth cone (41) and to reduce growth cone mobility and dendrite branching (42,43). The meaning of these latter actions in the physiology of learning is unclear.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of learning and memory after activation of cerebral Rho GTPases

Diana

Valentini

Travaglione

et al. 2007

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

119

115

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The mechanism whereby the morphology and connectivity of the dendritic tree is regulated depends on an actin dynamics that, in turn, is controlled by Rho GTPases, a family of small GTP-binding proteins encompassing Rho, Rac, and Cdc42 subfamilies. Cytotoxic necrotizing factor 1 (CNF1), a protein toxin from Escherichia coli, constitutively activates Rho GTPases, thus leading to remodeling of the actin cytoskeleton in intact cells. Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks. The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866. The results suggest that learning ability can be improved through pharmacological manipulation of neural connectivity.cytotoxic necrotizing factor 1 ͉ brain ͉ bacterial toxins ͉ dendritic spines ͉ drug therapy

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Section: Discussionmentioning

confidence: 99%

Enhancement of learning and memory after activation of cerebral Rho GTPases

Diana

Valentini

Travaglione

et al. 2007

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

119

115

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“…However, activation of the small GTPase RhoA appears to be a necessary step in mediating CSPG-associated inhibition in vitro. Several studies have reported disinhibition of neurite outgrowth on CSPG-rich substrates in the presence of ROCK inhibitors [54,55]. Therefore, blockade of the Rho/ROCK axis holds the potential to block signaling by myelin and CSPGs.…”

Section: Astroglial Scars and Cspgsmentioning

confidence: 99%

Axonal growth therapeutics: regeneration or sprouting or plasticity?

Cafferty

McGee

Strittmatter

2008

Trends in Neurosciences

142

108

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Loss of function after neurological injury frequently occurs through the interruption of axonal connectivity, rather than through cell loss. Functional deficits persist because a multitude of inhibitory factors in degenerating myelin and astroglial scar prevent axonal growth in the adult brain and spinal cord. Given the high clinical significance of achieving functional recovery through axonal growth, substantial research effort has been, and will be, devoted toward this desirable goal. Unfortunately, the labels commonly used in the literature to categorize post-injury axonal anatomy might hinder advancement. In this article, we present an argument for the importance of developing precise terms that describe axonal growth in terms of the inciting event, the distance of axonal extension and the timing of axonal growth. The phenotypes produced by molecular interventions that overcome astroglial scar or myelin-associated inhibitors are reframed and discussed in this context.

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“…HA1077 is in clinical use for managing cerebral vasospasm associated with subarachnoid hemorrhage and is under clinical trial for acute ischemic stroke [37], among other conditions. Application of Y27632 has also been investigated for promotion of neurite outgrowth and axonal regeneration [38][39][40][41][42][43][44][45] and inactivation of Rho or ROCK signaling promoted functional recovery and/or axonal regeneration after neural injuries [46][47][48].…”

Section: Introductionmentioning

confidence: 99%

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

et al. 2011

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Adult neural precursor cells (NPCs) in the subventricular zone (SVZ) normally migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB). Following neural injury, they also migrate to the site of damage. This study investigated the role of Rho-dependent kinase (ROCK) on the migration of NPCs in vitro and in vivo. In vitro, using neurospheres or SVZ explants, inhibition of ROCK using Y27632 promoted cell body elongation, process protrusion, and migration, while inhibiting NPC chain formation. It had no effect on proliferation, apoptosis, or differentiation. Both isoforms of ROCK were involved. Using siRNA, knockdown of both ROCK1 and ROCK2 was required to promote NPC migration and morphological changes; knockdown of ROCK2 alone was partially effective, with little/no effect of knockdown of ROCK1 alone. In vivo, infusion of Y27632 plus Bromodeoxyuridine (BrdU) into the lateral ventricle for 1 week reduced the number of BrdU-labeled NPCs in the OB compared with BrdU infusion alone. However, ROCK inhibition did not affect the tangential-to-radial switch of NPC migration, as labeled cells were present in all OB layers. The decrease in NPC number at the OB was not attributed to a decrease in NPCs at the SVZ. However, ROCK inhibition decreased the density of BrdU-labeled cells in the RMS and increased the distribution of these cells to ectopic brain regions, such as the accessory olfactory nucleus, where the majority differentiated into neurons. These findings suggest that ROCK signaling regulates NPC migration via regulation of cell-cell contact and chain migration.

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Suppression of Rho-kinase activity promotes axonal growth on inhibitory CNS substrates

Cited by 195 publications

References 50 publications

Enhancement of learning and memory after activation of cerebral Rho GTPases

Enhancement of learning and memory after activation of cerebral Rho GTPases

Axonal growth therapeutics: regeneration or sprouting or plasticity?

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

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