Rho GTPases as regulators of morphological neuroplasticity

Auer, Maria; Hausott, Barbara; Klimaschewski, Lars

doi:10.1016/j.aanat.2011.02.015

Cited by 67 publications

(65 citation statements)

References 108 publications

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“…Our results suggest that autophagy regulates axon growth via upregulation of the RhoA-ROCK pathway in developing neurons. RhoA and its downstream effector, ROCK, are well-known negative regulators of the early stages of axon extension in cultured neurons (72)(73)(74). Indeed, forced expression of the wild-type or constitutive active form of RhoA in autophagy-deficient neurons rescued the axon elongation phenotype caused by autophagy reduction.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Negatively Regulates Early Axon Growth in Cortical Neurons

Ban

Jun

Ryu

et al. 2013

Molecular and Cellular Biology

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c Neurite growth requires neurite extension and retraction, which are associated with protein degradation. Autophagy is a conserved bulk degradation pathway that regulates several cellular processes. However, little is known about autophagic regulation during early neurite growth. In this study, we investigated whether autophagy was involved in early neurite growth and how it regulated neurite growth in primary cortical neurons. Components of autophagy were expressed and autophagy was activated during early neurite growth. Interestingly, inhibition of autophagy by atg7 small interfering RNA (siRNA) caused elongation of axons, while activation of autophagy by rapamycin suppressed axon growth. Surprisingly, inhibition of autophagy reduced the protein level of RhoA. Moreover, expression of RhoA suppressed axon overelongation mediated by autophagy inhibition, whereas inhibition of the RhoA signaling pathway by Y-27632 recovered rapamycin-mediated suppression of axon growth. Interestingly, hnRNP-Q1, which negatively regulates RhoA, accumulated in autophagy-deficient neurons, while its protein level was reduced by autophagy activation. Overall, our study suggests that autophagy negatively regulates axon extension via the RhoA-ROCK pathway by regulating hnRNP-Q1 in primary cortical neurons. Therefore, autophagy might serve as a fine-tuning mechanism to regulate early axon extension.

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Section: Discussionmentioning

confidence: 99%

Autophagy Negatively Regulates Early Axon Growth in Cortical Neurons

Ban

Jun

Ryu

et al. 2013

Molecular and Cellular Biology

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“…Cdc42 deregulation has been linked to various aspects of tumorigenesis, including transformation and metastasis (3,39). Additionally, neuronal development and maintenance relies heavily on appropriate Cdc42 activity (8). Given the urgent need to discover an effective tool for Cdc42 study, we undertook a similar strategy in the discovery of NSC23766 and identified potential Cdc42 inhibitors by screening more than 197,000 small molecules coupled with biochemical and cell-based verifications.…”

Section: Discussionmentioning

confidence: 99%

“…Cdc42 has been attributed to several aspects of cancer, including cellular transformation (10) and metastasis (11,12). As a key regulator of neurite morphogenesis, Cdc42 has also been shown to be crucial for normal brain development, as conditional Cdc42 KO mice do not survive birth and show gross brain abnormalities (8,13).…”

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confidence: 99%

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Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

Friesland

Zhao

Chen

et al. 2013

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

152

148

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Signaling through the Rho family of small GTPases has been intensely investigated for its crucial roles in a wide variety of human diseases. Although RhoA and Rac1 signaling pathways are frequently exploited with the aid of effective small molecule modulators, studies of the Cdc42 subclass have lagged because of a lack of such means. We have applied high-throughput in silico screening and identified compounds that are able to fit into the surface groove of Cdc42, which is critical for guanine nucleotide exchange factor binding. Based on the interaction between Cdc42 and intersectin (ITSN), a specific Cdc42 guanine nucleotide exchange factor, we discovered compounds that rendered ITSN-like interactions in the binding pocket. By using in vitro binding and imaging as well as biochemical and cell-based assays, we demonstrated that ZCL278 has emerged as a selective Cdc42 small molecule modulator that directly binds to Cdc42 and inhibits its functions. In Swiss 3T3 fibroblast cultures, ZCL278 abolished microspike formation and disrupted GM130-docked Golgi structures, two of the most prominent Cdc42-mediated subcellular events. ZCL278 reduces the perinuclear accumulation of active Cdc42 in contrast to NSC23766, a selective Rac inhibitor. ZCL278 suppresses Cdc42-mediated neuronal branching and growth cone dynamics as well as actin-based motility and migration in a metastatic prostate cancer cell line (i.e., PC-3) without disrupting cell viability. Thus, ZCL278 is a small molecule that specifically targets Cdc42–ITSN interaction and inhibits Cdc42-mediated cellular processes, thus providing a powerful tool for research of Cdc42 subclass of Rho GTPases in human pathogenesis, such as those of cancer and neurological disorders.

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“…3B). NEP1-40, which acts as a selective, competitive and high affinity antagonist of NgR1 [38,39] was used to block NgR1 interaction with Nogo-p4. Results showed that while Nogo-p4 inhibited NGF-induced neurite growth by 52%, NEP1-40 significantly attenuated the inhibition by 37% (Fig.…”

Section: Figmentioning

confidence: 99%

Nogo-p4 Suppresses TrkA Signaling Induced by Low Concentrations of Nerve Growth Factor Through NgR1 in Differentiated PC12 Cells

Fan

Huang

et al. 2016

Neurosignals

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Background: Regeneration of injured axons in adult mammalian central nervous system (CNS) is not spontaneous. Nogo is a major inhibitory molecule contributing to axon regeneration failure. The molecular mechanisms of Nogo inhibition of axon regeneration are not completely understood. To further investigate the underlying mechanisms, we studied the effects of Nogo-p4, a 25-amino acid core inhibitory fragment of Nogo, on nerve growth factor (NGF)-induced TrkA signaling. Methods: NGF-differentiated PC12 cells were used as cell models. The effects of Nogo-p4 on two key components of TrkA signaling, phosphorylated Erk1/2 and Akt, were analyzed by western blot. Co-immunoprecipitation experiments were performed to detect the formation of NgR1/p75 complexes. Neurite growth was quantified by measuring the neurite length. Results: Nogo-p4 did not significantly affect TrkA signaling induced by 100 ng/ml NGF, but signaling was suppressed when an NGF concentration of 5 ng/ml was used. Further investigation demonstrated that Nogo-p4 affected TrkA signaling in an NGF concentration-dependent manner. Nogo-p4 suppression of TrkA signaling was strong at low (1 and 5 ng/ml), moderate at intermediate (25 ng/ml), but absent at high (50 and 100 ng/ml) NGF concentrations. NEP1-40 attenuated, and NgR1 overexpression enhanced, Nogo-p4 suppression of TrkA signaling induced by low concentrations of NGF. High but not low concentrations of NGF reduced the formation of NgR1/p75 complexes triggered by Nogo-p4. Nogo-p4 strongly inhibited neurite growth induced by low rather than high concentrations of NGF. Conclusion: Nogo-p4 binding with NgR1 suppresses TrkA signaling induced by low concentrations of NGF in differentiated PC12 cells. Suppression of NGF-induced TrkA signaling may be another mechanism by which Nogo inhibits neurite growth.

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Rho GTPases as regulators of morphological neuroplasticity

Cited by 67 publications

References 108 publications

Autophagy Negatively Regulates Early Axon Growth in Cortical Neurons

Autophagy Negatively Regulates Early Axon Growth in Cortical Neurons

Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

Nogo-p4 Suppresses TrkA Signaling Induced by Low Concentrations of Nerve Growth Factor Through NgR1 in Differentiated PC12 Cells

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