RhoG Promotes Neural Progenitor Cell Proliferation in Mouse Cerebral Cortex

Fujimoto, Satoshi; Negishi, Manabu; Katoh, Hironori

doi:10.1091/mbc.e09-03-0200

Cited by 24 publications

(31 citation statements)

References 53 publications

(52 reference statements)

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“…At a mid-gestational stage of embryonic development (E14.5), the cerebral cortex of SOD−/− mice appeared smaller than wild type control embryos. To determine the extent to which the cells in each layer in a radial unit of the developing cortex differed in SOD−/− and wild type embryos, we examined the frontal cortex in coronal sections immunostained with Tuj1 (a marker of differentiated neurons) and Ki67 (a marker of proliferative cells which are exclusively NPCs at this specific developmental stage) (37, 38). In both wild type and SOD2−/− embryos, Ki67+ and Tuj1+ cells demark a clear germinal zone (proliferative zone) and zones of differentiated neurons (intermediate and cortical plate zones), respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development

et al. 2012

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Although high amounts of reactive oxygen species (ROS) can damage cells, ROS can also play roles as second messengers, regulating diverse cellular processes. Here we report that embryonic mouse cerebral cortical neural progenitor cells (NPCs) exhibit intermittent spontaneous bursts of mitochondrial superoxide (SO) generation (mitochondrial SO flashes) that require transient opening of membrane permeability transition pores (mPTP). This quantal SO production negatively regulates NPC self-renewal. Mitochondrial SO scavengers and mPTP inhibitors reduce SO flash frequency and enhance NPC proliferation, whereas prolonged mPTP opening and SO generation increase SO flash incidence and decrease NPC proliferation. The inhibition of NPC proliferation by mitochondrial SO involves suppression of extracellular signal-regulated kinases. Moreover, mice lacking SOD2 (SOD2−/− mice) exhibit significantly fewer proliferative NPCs and differentiated neurons in the embryonic cerebral cortex at mid-gestation compared with wild type littermates. Cultured SOD2−/− NPCs exhibit a significant increase in SO flash frequency and reduced NPC proliferation. Taken together, our findings suggest that mitochondrial SO flashes negatively regulate NPC self-renewal in the developing cerebral cortex.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development

et al. 2012

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“…As RhoG has been shown to promote the proliferation of neural progenitor cells in the mouse cerebral cortex [21], we also examined whether RhoG contributes to the proliferative behavior of glioblastoma cells, as this could be a possible confounding factor in the evaluation of glioblastoma cell invasiveness. We observed that depletion of RhoG has a small inhibitory effect on the proliferation of glioblastoma cells over a 5 day period in the presence of serum, but does not affect cell proliferation over the time period in which the brain slice invasion experiments are carried out (2 days) (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

The small GTPase RhoG mediates glioblastoma cell invasion

et al. 2012

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BackgroundThe invasion of glioblastoma cells into regions of the normal brain is a critical factor that limits current therapies for malignant astrocytomas. Previous work has identified roles for the Rho family guanine nucleotide exchange factors Trio and Vav3 in glioblastoma invasion. Both Trio and Vav3 act on the small GTPase RhoG. We therefore examined the role of RhoG in the invasive behavior of glioblastoma cells.ResultsWe found that siRNA-mediated depletion of RhoG strongly inhibits invasion of glioblastoma cells through brain slices ex vivo. In addition, depletion of RhoG has a marginal effect on glioblastoma cell proliferation, but significantly inhibits glioblastoma cell survival in colony formation assays. We also observed that RhoG is activated by both HGF and EGF, two factors that are thought to be clinically relevant drivers of glioblastoma invasive behavior, and that RhoG is overexpressed in human glioblastoma tumors versus non-neoplastic brain. In search of a mechanism for the contribution of RhoG to the malignant behavior of glioblastoma cells, we found that depletion of RhoG strongly inhibits activation of the Rac1 GTPase by both HGF and EGF. In line with this observation, we also show that RhoG contributes to the formation of lamellipodia and invadopodia, two functions that have been shown to be Rac1-dependent.ConclusionsOur functional analysis of RhoG in the context of glioblastoma revealed a critical role for RhoG in tumor cell invasion and survival. These results suggest that targeting RhoG-mediated signaling presents a novel avenue for glioblastoma therapy.

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“…For the TUNEL assay, hippocampal neurons were transfected with the indicated plasmids at 11 DIV using Lipofectamine 2000 and fixed at 15 DIV. The TUNEL assay was performed as described previously (49).…”

Section: Methodsmentioning

confidence: 99%

The F-BAR Protein Rapostlin Regulates Dendritic Spine Formation in Hippocampal Neurons

Wakita

Kakimoto

Katoh

et al. 2011

Journal of Biological Chemistry

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Pombe Cdc15 homology proteins, characterized by Fer/CIP4 homology Bin-Amphiphysin-Rvs/extended Fer/CIP4 homology (F-BAR/EFC) domains with membrane invaginating property, play critical roles in a variety of membrane reorganization processes. Among them, Rapostlin/formin-binding protein 17 (FBP17) has attracted increasing attention as a critical coordinator of endocytosis. Here we found that Rapostlin was expressed in the developing rat brain, including the hippocampus, in late developmental stages when accelerated dendritic spine formation and maturation occur. In primary cultured rat hippocampal neurons, knockdown of Rapostlin by shRNA or overexpression of Rapostlin-QQ, an F-BAR domain mutant of Rapostlin that has no ability to induce membrane invagination, led to a significant decrease in spine density. Expression of shRNA-resistant wild-type Rapostlin effectively restored spine density in Rapostlin knockdown neurons, whereas expression of Rapostlin deletion mutants lacking the protein kinase C-related kinase homology region 1 (HR1) or Src homology 3 (SH3) domain did not. In addition, knockdown of Rapostlin or overexpression of Rapostlin-QQ reduced the uptake of transferrin in hippocampal neurons. Knockdown of Rnd2, which binds to the HR1 domain of Rapostlin, also reduced spine density and the transferrin uptake. These results suggest that Rapostlin and Rnd2 cooperatively regulate spine density. Indeed, Rnd2 enhanced the Rapostlin-induced tubular membrane invagination. We conclude that the F-BAR protein Rapostlin, whose activity is regulated by Rnd2, plays a key role in spine formation through the regulation of membrane dynamics.

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RhoG Promotes Neural Progenitor Cell Proliferation in Mouse Cerebral Cortex

Cited by 24 publications

References 53 publications

Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development

Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development

The small GTPase RhoG mediates glioblastoma cell invasion

The F-BAR Protein Rapostlin Regulates Dendritic Spine Formation in Hippocampal Neurons

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