Myosin II activity regulates neurite outgrowth and guidance in response to chondroitin sulfate proteoglycans

Santiago, Lizzie Y.; Katagiri, Yasuhiro; Geller, Herbert M.

doi:10.1111/j.1471-4159.2011.07638.x

Cited by 44 publications

(38 citation statements)

References 39 publications

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“…When under injury, F-actin is reported to polymerize at the distal end of injured neuritis and undergoes reorganization and retrograde flow generated by myosin II, the actin-binding motor protein 48, 49. The two isoforms of myosin undertake distinct roles: myosin IIB functions as the molecular motor responsible for neurite outgrowth, while myosin IIA maintains focal contact formation and drives neurite retraction 50-52.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization

Wang

Liu

et al. 2016

Int. J. Biol. Sci.

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Oxidative stress-induced cytoskeletal dysfunction of neurons has been implicated as a crucial cause of cell apoptosis or death in the central nervous system (CNS) diseases, such as neurodegenerative and psychiatric diseases. The application of neuroprotectants rescuing the neurons from cytoskeletal damage and apoptosis can be a potential treatment for these CNS diseases. Ginsenoside Rg1 (Rg1), one of the major active components of ginseng, has been reported possessing notable neuroprotective activities. However, there is rare report about its effect on cytoskeleton and its undergoing mechanism. The current study is to reveal the regulatory effects of Rg1 on cytoskeletal and morphological lesion in oxidative stress-induced neuronal apoptosis. The results demonstrated that pre-treatment with Rg1 (0.1-10 μM) attenuated hydrogen peroxide (H2O2)-induced neuronal apoptosis and oxidative stress through reducing the intracellular reactive oxygen species (ROS) production and methane dicarboxylic aldehyde (MDA) level. The Rg1 treatment also abolished H2O2-induced morphological changes, including cell rounding, membrane blebbing, neurite retraction and nuclei condensation, which were generated by myosin IIA-actin interaction. These effects were mediated via the down-regulation of caspase-3, ROCK1 (Rho-associated kinase1) activation and myosin light chain (MLC, Ser-19) phosphorylation. Furthermore, inhibiting myosin II activity with blebbistatin partly blocked the neuroprotective effects of Rg1. The computer-aided homology modelling revealed that Rg1 preferentially positioned in the actin binding cleft of myosin IIA and might block the binding of myosin IIA to actin filaments. Accordingly, the neuroprotective mechanism of Rg1 is related to the activity that inhibits myosin IIA-actin interaction and the caspase-3/ROCK1/MLC signaling pathway. These findings put some insights into the unique neuroprotective properties of Rg1 associated with the regulation of myosin IIA-actin cytoskeletal structure under oxidative stress and provide experimental evidence for Rg1 in CNS diseases.

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Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization

Wang

Liu

et al. 2016

Int. J. Biol. Sci.

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“…Multiple studies have reported insights into the mechanisms involved in the regulation of CSPG inhibition, such as myosin II (Yu et al, 2011) and EGFR (Koprivica et al, 2005), along with signaling pathways involving Akt (Fisher et al, 2011) and integrins (Tan et al, 2011). In future studies it will be important to elucidate additional intrinsic properties that may be unique to the insensitivity of NRP-derived neurons to CSPGs.…”

Section: Discussionmentioning

confidence: 99%

The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition

Ketschek

Haas

Gallo

et al. 2012

Experimental Neurology

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The extension of axons through the major inhibitory component of the glial scar, chondroitin sulfate proteoglycans (CSPG), remains a key obstacle for regeneration following spinal cord injury (SCI). We have previously shown that transplants composed of neuronal and glial restricted precursors (NRP and GRP respectively) promote regeneration and connectivity in the injured spinal cord (Bonner et al., 2010; 2011), however, little is known about the properties of these precursors at a cellular level. We now report that NRP-derived neurons, in contrast to dorsal root ganglion (DRG) neurons, have the ability to extend axons and cross over from a permissive substratum (laminin) onto inhibitory CSPG in vitro. Growth cones of neurons derived from NRP, compared to DRG, exhibit significantly lower levels of the CSPG receptors protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR). GRP-conditioned medium prepared from the same cell densities did not affect the response of primary sensory neurons to CSPG confirming that the ability of NRP-derived neurons to cross onto CSPG is determined intrinsically. However, GRP-conditioned medium collected from high density cultures increased the probability of DRG axons to cross from LN onto CSPG and increased the length of DRG axons extending on CSPG. Collectively, these results suggest that (1) neurons derived from NRPs are intrinsically insensitive to CSPGs due to low levels of receptor expression, and (2) high levels of factors secreted by GRP can reduce the inhibitory effects of CSPG and promote axonal growth. These observations provide mechanistic insights into the specific roles of NRPs and GRPs in promoting regeneration and repair following SCI.

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“…Myosin II, an ATP-dependent motor protein, appears to mediate CSPG inhibition on neuronal growth (Hur et al, 2011; Yu et al, 2012). CSPGs increase phosphorylation of nonmuscle myosin II regulatory light chains and pharmacological or genetic inhibition of myosin II promotes axon growth on inhibitory substrates including CSPGs.…”

Section: Downstream Signaling Pathways That Convey Growth Inhibitimentioning

confidence: 99%

Molecular mechanisms of scar-sourced axon growth inhibitors

Ohtake

2015

Brain Research

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Astrogliosis is a defense response of the CNS to minimize primary damage and to repair injured tissues, but it ultimately generates harmful effects by upregulating inhibitory molecules to suppress neuronal elongation and forming potent barriers to axon regeneration. Chondroitin sulfate proteoglycans (CSPGs) are highly expressed by reactive scars and are potent contributors to the non-permissive environment in mature CNS. Surmounting strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. Currently, enzymatic digestion of CSPGs with locally applied chondroitinase ABC is the main in vivo approach to overcome scar inhibition, but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of molecular mechanisms underlying CSPG function may facilitate development of new effective therapies to overcome scar-mediated inhibition. Previous studies support that CSPGs act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions, but two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibition. CSPGs may also act by binding two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3. Thus, CSPGs inhibit axon growth through multiple mechanisms, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries.

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Myosin II activity regulates neurite outgrowth and guidance in response to chondroitin sulfate proteoglycans

Cited by 44 publications

References 39 publications

Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization

Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization

The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition

Molecular mechanisms of scar-sourced axon growth inhibitors

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