The role of Rho GTPases and associated kinases in regulating neurite outgrowth

doi:10.1016/S1357-2725(01)00167-4

The International Journal of Biochemistry & Cell Biology

Volume 34, Issue 7, July 2002, Pages 731-745

https://doi.org/10.1016/S1357-2725(01)00167-4 Get rights and content

Abstract

Neurones are highly specialised cells that can extend over great distances, enabling the complex networking of the nervous system. We are beginning to understand in detail the molecular mechanisms that control the shape of neurones during development. One family of proteins that are clearly essential are the Rho GTPases which have a pivotal role in regulating the actin cytoskeleton in all cell types. The Rho GTPases are responsible for the activation and downregulation of many downstream kinases. This review discusses individual kinases that are regulated by three members of the Rho GTPases, Rac, Rho and Cdc42 and their function during neurite outgrowth and remodelling.

Introduction

Since the discovery in the mid 1980s and early 1990s that three members of the Rho family of small GTPases (Rac1, RhoA and Cdc42) function to regulate the actin cytoskeleton, many research laboratories have examined if they control the movement and shape of their favourite cell types. Their biological function was initially described in Swiss 3T3 fibroblasts where Rac1 induces the formation of sheet-like structures (lamellipodia), Cdc42 causes the formation of cell surface microspikes (filopodia), while RhoA enhances cell attachment and contractility [1], [2], [3]. The Rho GTPases have since then been shown to control different aspects of the cellular cytoskeleton, largely dependent on the cell types studied. Rac1, RhoA and Cdc42 switch between an active and an inactive state in a highly regulated manner. The active forms function to trigger downstream signalling pathways, many of which are dominated by kinase cascades [4]. The past few years have seen a tremendous amount of new information on the regulation and function of these three proteins in neurones and non-neuronal cells (for recent reviews see, [5], [6], [7], [8], [9], [10]). In neurones it has become largely apparent that Rac1 and Cdc42 induce, while RhoA inhibits neurite outgrowth [6]. However, more work needs to be carried out to understand the relationship between these three proteins in different neurones and whether it is subject to temporal and spatial regulation. In addition to neurite outgrowth, these small GTPases have been shown to control the establishment of neuronal polarity, neuronal migration, growth cone guidance and the function of synapses [6], [7]. Together, the Rho family of small GTPases can regulate every process in a neurone that involves plasticity of the cytoskeleton. This review focuses on studies that have addressed the function of Rac1, RhoA and Cdc42 and downstream kinases in primary neurones both in vitro and in vivo.

Section snippets

The Rho GTPases and neurite outgrowth

A neurone is the highly specialised, basic unit of the functioning nervous system. It transports information to other neurones and non-neuronal cells, enabling the co-ordinated functioning of an organism. Neurones have a highly polarised morphology, with a single long process termed the axon and often many short neurites known as dendrites (Fig. 1). Information is usually received at the dendrites, transported through the cell and delivered further via the axon. For the nervous system to

The p35/Cdk5 kinase

Cdk5 is a member of the cyclin dependent kinase (Cdk) family, which are proline directed serine/threonine kinases that require the association of a regulatory protein for activity [50]. Cdk5 is activated in postmitotic neurones by two highly related proteins, p35 and p39 [51]. The p35 and p39 are to date the only known Cdk5 kinase activators. Whereas, Cdk5 is ubiquitously expressed, p35 and p39 are induced upon cellular differentiation and not detectable in proliferating cells [51]. For a long

Kinases regulated by RhoA

The most studied RhoA effectors are the serine/threonine Rho-associated kinases. Whereas, ROKβ/ROCK1 expression is hardly detectable in brain, ROKα/Rho-kinase/ROCK2/p160ROCK is highly enriched in pyramidal neurones of the cortex and hippocampus and cerebellar Purkinje neurones [91]. Both proteins have an N-terminal kinase domain and C-terminal RhoGTP binding and autoinhibitory domains. In an analogous way to the Pak kinases, Rho associated kinases exist in an autoinhibited state, which is

Kinases regulated by Cdc42

Much less is known about the kinases that function downstream from Cdc42 in neurones. The most studied are Pak1, Pak2 and Pak3, although they have primarily been examined as targets of Rac1, rather than Cdc42. Because both Rac1 and Cdc42 appear to regulate these Pak kinases indistinguishably from each other and Rac1 can be activated by Cdc42, it is hard to separate the effects of these two GTPases on Pak1, Pak2 and Pak3 kinases in vivo. An interesting model has been put forward suggesting that

If only it was this simple

It is becoming increasingly apparent that the Rho GTPases often have opposing roles in regulating the neuronal cytoskeleton and that the same signals that activate one, cause the downregulation of another. Currently, the best examples are Rac1 and RhoA and their differential regulation by the ephrins and semaphorins [37], [38], [40], [41]. Overall, it is clear that these molecules do not work in isolation and signalling pathways that emanate from them converge. Figuring out exactly what kinases

What the future holds

The aim of this review was to sum up and simplify a lot of complex signalling pathways and describe what is known to date on how they may modulate the cytoskeleton in postmitotic, differentiating neurones. Particular emphasis was made on neurite outgrowth and remodelling. It is apparent that the correct wiring of the nervous system is governed by the maintenance of a fine balance between seemingly opposing signals and that localised and transient changes dictate processes such as growth cone

Acknowledgements

Due to space limitations I have not been able to describe all the contributions researchers have made to this field and I apologise to the authors whose work has not been mentioned. I would like to thank Britta Eickholt (King’s College London) for helpful discussions and critically reading this manuscript. Work in the author’s laboratory is supported by the Wellcome Trust, The BBSRC and Glaxo–SmithKline.

References (132)

A.J. Ridley et al.
The small GTP-binding protein Rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors
Cell
(1992)
A.J. Ridley et al.
The small GTP-binding protein Rac regulates growth factor-induced membrane ruffling
Cell
(1992)
C.D. Nobes et al.
Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia
Cell
(1995)
A.J. Ridley, Rho, Oxford University Press, 2000, pp....
A. Hall et al.
Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton
Philos. Trans. R. Soc. London B. Biol. Sci.
(2000)
L. Luo
Rho GTPases in neuronal morphogenesis
Nat. Rev. Neurosci.
(2000)
B.J. Dickson
Rho GTPases in growth cone guidance
Curr. Opin. Neurobiol.
(2001)
D. Bar-Sagi et al.
Ras and Rho GTPases: a family reunion
Cell
(2000)
L. Redmond et al.
The role of Notch and Rho GTPase signaling in the control of dendritic development
Curr. Opin. Neurobiol.
(2001)
A.A. Schmitz et al.
Rho GTPases: signaling, migration, and invasion
Exp. Cell Res.
(2000)

B.K. Mueller

Growth cone guidance: first steps towards a deeper understanding

Annu. Rev. Neurosci.

(1999)

F. Nakamura et al.

Molecular basis of semaphorin-mediated axon guidance

J. Neurobiol.

(2000)

J.A. Raper

Semaphorins and their receptors in vertebrates and invertebrates

Curr. Opin. Neurobiol.

(2000)

C.M. Waterman-Storer et al.

Positive feedback interactions between microtubule and actin dynamics during cell motility

Curr. Opin. Cell Biol.

(1999)

N. Kobayashi et al.

A role of microtubules during the formation of cell processes in neuronal and non-neuronal cells

Cell Tissue Res.

(1998)

P.W. Baas

Microtubules and neuronal polarity: lessons from mitosis

Neuron

(1999)

L. Van Aelst et al.

Rho GTPases and signaling networks

Genes Dev.

(1997)

M.R. Alam et al.

Kalirin, a cytosolic protein with spectrin-like and GDP/GTP exchange factor-like domains that interacts with peptidylglycine alpha-amidating monooxygenase, an integral membrane peptide-processing enzyme

J. Biol. Chem.

(1997)

P. Billuart et al.

Oligophrenin-1 encodes a RhoGAP protein involved in X-linked mental retardation

Nature

(1998)

M.R. Brouns et al.

p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation

Nat. Cell Biol.

(2001)

G.G. Habets et al.

Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP–GTP exchangers for Rho-like proteins

Cell

(1994)

C. Hall et al.

alpha2-chimaerin, a Cdc42/Rac1 regulator, is selectively expressed in the rat embryonic nervous system and is involved in neuritogenesis in N1E-115 neuroblastoma cells

J. Neurosci.

(2001)

Y. Horii et al.

A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways

EMBO J.

(1994)

M. Hoshino et al.

Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1

J. Biol. Chem.

(1999)

E. Ehler et al.

Expression of Tiam-1 in the developing brain suggests a role for the Tiam-1-Rac signaling pathway in cell migration and neurite outgrowth

Mol. Cell Neurosci.

(1997)

X.M. Ma et al.

Expression of kalirin, a neuronal GDP/GTP exchange factor of the trio family, in the central nervous system of the adult rat

J. Comp. Neurol.

(2001)

C.N. Adra et al.

RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas

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

(1997)

S.S. Andersen et al.

Axon formation: a molecular model for the generation of neuronal polarity

Bioessays

(2000)

F. Bradke et al.

The role of local actin instability in axon formation

Science

(1999)

M.L. Ruchhoeft et al.

The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo

J. Neurosci

(1999)

T.B. Kuhn et al.

Rac1-dependent actin filament organization in growth cones is necessary for beta1-integrin-mediated advance but not for growth on poly-d-lysine

J. Neurobiol.

(1998)

L. Luo et al.

Small GTPases in axon outgrowth

Perspect. Dev. Neurobiol.

(1996)

T. Lee et al.

Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis

Neuron

(2000)

R. Threadgill et al.

Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42

Neuron

(1997)

D.G. Wilkinson

Multiple roles of EPH receptors and ephrins in neural development

Nat. Rev. Neurosci.

(2001)

M. Nakamoto

Eph receptors and ephrins

Int. J. Biochem. Cell Biol.

(2000)

S. Wahl et al.

Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase

J. Cell Biol.

(2000)

S.M. Shamah et al.

EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin

Cell

(2001)

K.L. Whitford et al.

Plexin signaling via off-track and Rho family GTPases

Neuron

(2001)

M.H. Driessens et al.

Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho

Curr. Biol.

(2001)

H. Hu et al.

Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling

Neuron

(2001)

H.G. Vikis et al.

The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner

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

(2000)

L. Luo et al.

Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion

Genes Dev.

(1994)

N. Kaufmann et al.

Drosophila Rac1 controls motor axon guidance

Development

(1998)

Z. Li et al.

Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo

Nat. Neurosci.

(2000)

L. Luo et al.

Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines

Nature

(1996)

I. Arozarena et al.

Maintenance of CDC42 GDP-bound state by Rho-GDI inhibits MAP kinase activation by the exchange factor Ras-GRF. evidence for Ras-GRF function being inhibited by Cdc42-GDP but unaffected by CDC42-GTP

J. Biol. Chem.

(2001)

N. Di-Poi et al.

Mechanism of NADPH oxidase activation by the Rac/Rho-GDI complex

Biochemistry

(2001)

J.Z. Tsien et al.

The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory

Cell

(1996)

M. Meyerson et al.

A family of human cdc2-related protein kinases

EMBO J.

(1992)

Cited by (119)

The role of Actopaxin in tumor metastasis
2022, Progress in Biophysics and Molecular Biology
Citation Excerpt :
It is not only an important modulator of integrin-induced Rho family signaling transduction to the cytoskeleton, but also an important negative regulator of adhesion-dependent signaling. Besides, CdGAP also works as an inhibitor of lamellipodia formation induced by growth factors (LaLonde et al., 2006; Sun et al., 2004; Nikolic, 2002; Chen et al., 2000; Mehra et al., 2021). CdGAP interacts directly to the amino terminal of Actopaxin through its central domain to regulate integrin-dependent changes in cell morphology and motility (LaLonde et al., 2006; Jenna et al., 2002).
Actopaxin is a newly discovered focal adhesions (FAs) protein, actin-binding protein and pseudopodia-enriched molecule. It can not only bind to a variety of FAs proteins (such as Paxillin, ILK and PINCH) and non-FAs proteins (such as TESK1, CdGAP, β2-adaptin, G3BP2, ADAR1 and CD29), but also participates in multiple signaling pathways. Thus, it plays a crucial role in regulating important processes of tumor metastasis, including matrix degradation, migration, and invasion, etc. This review covers the latest progress in the structure and function of Actopaxin, its interaction with other proteins as well as its involvement in regulating tumor development and metastasis. Additionally, the current limitations for Actopaxin related studies and the possible research directions on it in the future are also discussed. It is hoped that this review can assist relevant researchers to obtain a deep understanding of the role that Actopaxin plays in tumor progression, and also enlighten further research and development of therapeutic approaches for the treatment of tumor metastasis.
Diacylglycerol kinase β induces filopodium formation via its C1, catalytic and carboxy-terminal domains and interacts with the Rac1-GTPase-activating protein, β2-chimaerin
2018, Biochemical and Biophysical Research Communications
The β-isoform of diacylglycerol kinase (DGK) localizes predominantly to neurons and induces neurite outgrowth and spine formation. However, the detailed molecular mechanisms underlying the functions of DGKβ remain elusive. During the course of studies on other DGK isozymes, we unexpectedly found that the overexpression of wild-type DGKβ in COS-7 cells markedly induced filopodium formation. Because filopodium formation is closely related to neurite outgrowth and spine formation, we constructed various DGKβ mutants and compared their abilities to induce filopodium formation in order to elucidate the structure-function relationships of DGKβ. We found that the C-terminal, C1 and catalytic domains and catalytic activity were indispensable for filopodium formation, but the recoverin homology domain and EF-hand motifs were not. Moreover, the extent of plasma membrane localization and F-actin colocalization were positively correlated with filopodium formation. Intriguingly, DGKβ selectively interacted and colocalized at the plasma membrane with a Rac1-GTPase-activating protein, β2-chimaerin, which is an inducer of filopodia; it also interacted, to lesser extent, with α2-chimaerin, but not with α1- or β1-chimaerin. Moreover, DGKβ enhanced the plasma membrane localization of β2-chimaerin. These results suggest that DGKβ plays an important role in neurite outgrowth and spine formation in neurons via its ability to induce filopodium formation.
Neuronal adaptor FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1
2018, Journal of Biological Chemistry
Neurite outgrowth is a crucial process in developing neurons for neural network formation. Understanding the regulatory mechanisms of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration after nerve injury and in neurodegenerative disorders. FE65 is a brain-enriched adaptor that stimulates Rac1-mediated neurite elongation. However, the precise mechanism by which FE65 promotes the process remains elusive. Here, we show that ELMO1, a subunit of ELMO1-DOCK180 bipartite Rac1 guanine nucleotide exchange factor (GEF), interacts with the FE65 N-terminal region. Overexpression of FE65 and/or ELMO1 enhances, whereas knockdown of FE65 or ELMO1 inhibits, neurite outgrowth and Rac1 activation. The effect of FE65 alone or together with ELMO1 is attenuated by an FE65 double mutation that disrupts FE65-ELMO1 interaction. Notably, FE65 is found to activate ELMO1 by diminishing ELMO1 intramolecular autoinhibitory interaction and to promote the targeting of ELMO1 to the plasma membrane, where Rac1 is activated. We also show that FE65, ELMO1, and DOCK180 form a tripartite complex. Knockdown of DOCK180 reduces the stimulatory effect of FE65-ELMO1 on Rac1 activation and neurite outgrowth. Thus, we identify a novel mechanism by which FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1.
An Orchestra of Reovirus Receptors: Still Searching for the Conductor
2018, Advances in Virus Research
Citation Excerpt :
NgR1 lacks a cytoplasmic domain and likely is incapable of intraneuronal signaling without cytoplasmic-domain-containing coreceptors. Under physiological conditions, NgR1 binds myelin-associated ligands and recruits two neural coreceptors to form a tripartite complex that initiates RhoA activation and actin reorganization to prevent axonal outgrowth (Nikolic, 2002). Many other viruses hijack the Rho pathway during entry (Taylor et al., 2011), but it is not known whether reovirus binding to NgR1 initiates signaling events or ligation of coreceptors.
Viruses are constantly engaged in a molecular arms race with the host, where efficient and tactical use of cellular receptors benefits critical steps in infection. Receptor use dictates initiation, establishment, and spread of viral infection to new tissues and hosts. Mammalian orthoreoviruses (reoviruses) are pervasive pathogens that use multiple receptors to overcome protective host barriers to disseminate from sites of initial infection and cause disease in young mammals. In particular, reovirus invades the central nervous system (CNS) with serotype-dependent tropism and disease. A single viral gene, encoding the attachment protein σ1, segregates with distinct patterns of CNS injury. Despite the identification and characterization of several reovirus receptors, host factors that dictate tropism via interaction with σ1 remain undefined. Here, we summarize the state of the reovirus receptor field and discuss open questions toward understanding how the reovirus attachment protein dictates CNS tropism.
Arhgef1 is expressed in cortical neural progenitor cells and regulates neurite outgrowth of newly differentiated neurons
2017, Neuroscience Letters
Neurite outgrowth is crucial for the maturation of neurons and the establishment of anatomical connections during development of the nervous system. We report here that Arhgef1, a RhoA guanine nucleotide exchange factor previously found expressed in the early stages of neuronal development to regulate neurite outgrowth, is also highly expressed in cortical neural progenitor cells (NPCs). To better dissect its role in NPCs, we knocked down Arhgef1 expression in these cells and induced differentiated of them into neurons. Notably, silencing of Arhgef1 markedly enhanced neurite outgrowth in neurons derived from NPCs. Furthermore, we showed that Arhgef1 silencing inhibited the activity of RhoA, and pharmacological blockade of RhoA activity promoted neurite outgrowth in NPC-derived neurons. These findings reveal that Arhgef1 controls the process of neurite formation in newborn cortical neurons derived from NPCs.
Multitarget intervention of Fasudil in the neuroprotection of dopaminergic neurons in MPTP-mouse model of Parkinson's disease
2015, Journal of the Neurological Sciences
Recent studies have demonstrated that activation of the Rho-associated kinase (ROCK) pathway participates in the dopaminergic neuron degeneration and possibly in Parkinson's disease (PD). In the current study, we tried to observe the therapeutic potential of ROCK inhibitor Fasudil against dopaminergic neuron injury in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model of PD, and explore possible molecular mechanisms by enzyme-linked immunosorbent assay (ELISA), western blot and immunofluorescent assays. The results showed that MPTP-PD mice presented motor deficits, dopaminergic neuron loss, activation of inflammatory response and oxidative stress as well as ROCK and glycogen synthase kinase 3β (GSK-3β) signaling pathways. The administration of Fasudil exhibited neuroprotective effects against the dopaminergic neurons and improved the motor function recovery in the MPTP-PD mice, accompanied by the suppression of inflammatory responses (IL-1β, TNF-α, NF-κB-p65 and TLR-2), and oxidative stress (iNOS and gp91Phox), which might be associated with the inhibition of ROCK and GSK-3β activity. Simultaneously, the administration of Fasudil resulted in the shift from inflammatory M1 to anti-inflammatory/neurorepair M2 microglia. Additionally, Fasudil intervention enhanced the expression of anti-oxidative factors such as NF-E2-related factor 2 (Nrf2), Hmox as well as neurotrophic factor including GDNF. Our observations defined the neuroprotective effects of Fasudil in MPTP-PD mice, and we found a series of novel effector molecules and pathways for explaining the neuroprotective effects against dopaminergic neurons. However, a lot of investigations are warranted to further elucidate the crosstalk among Fasudil, oxidative stress, inflammatory response, GDNF and ROCK/NF-kB/Nrf2 pathways in the therapeutic potential of PD.

View all citing articles on Scopus

View full text

ReviewThe role of Rho GTPases and associated kinases in regulating neurite outgrowth

Abstract

Introduction

Section snippets

The Rho GTPases and neurite outgrowth

The p35/Cdk5 kinase

Kinases regulated by RhoA

Kinases regulated by Cdc42

If only it was this simple

What the future holds

Acknowledgements

The small GTP-binding protein Rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors

Cell

The small GTP-binding protein Rac regulates growth factor-induced membrane ruffling

Cell

Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia

Cell

Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton

Philos. Trans. R. Soc. London B. Biol. Sci.

Rho GTPases in neuronal morphogenesis

Nat. Rev. Neurosci.

Rho GTPases in growth cone guidance

Curr. Opin. Neurobiol.

Ras and Rho GTPases: a family reunion

Cell

The role of Notch and Rho GTPase signaling in the control of dendritic development

Curr. Opin. Neurobiol.

Rho GTPases: signaling, migration, and invasion

Exp. Cell Res.

Growth cone guidance: first steps towards a deeper understanding

Annu. Rev. Neurosci.

Molecular basis of semaphorin-mediated axon guidance

J. Neurobiol.

Semaphorins and their receptors in vertebrates and invertebrates

Curr. Opin. Neurobiol.

Positive feedback interactions between microtubule and actin dynamics during cell motility

Curr. Opin. Cell Biol.

A role of microtubules during the formation of cell processes in neuronal and non-neuronal cells

Cell Tissue Res.

Microtubules and neuronal polarity: lessons from mitosis

Neuron

Rho GTPases and signaling networks

Genes Dev.

Kalirin, a cytosolic protein with spectrin-like and GDP/GTP exchange factor-like domains that interacts with peptidylglycine alpha-amidating monooxygenase, an integral membrane peptide-processing enzyme

J. Biol. Chem.

Oligophrenin-1 encodes a RhoGAP protein involved in X-linked mental retardation

Nature

p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation

Nat. Cell Biol.

Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP–GTP exchangers for Rho-like proteins

Cell

alpha2-chimaerin, a Cdc42/Rac1 regulator, is selectively expressed in the rat embryonic nervous system and is involved in neuritogenesis in N1E-115 neuroblastoma cells

J. Neurosci.

A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways

EMBO J.

Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1

J. Biol. Chem.

Expression of Tiam-1 in the developing brain suggests a role for the Tiam-1-Rac signaling pathway in cell migration and neurite outgrowth

Mol. Cell Neurosci.

Expression of kalirin, a neuronal GDP/GTP exchange factor of the trio family, in the central nervous system of the adult rat

J. Comp. Neurol.

RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas

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

Axon formation: a molecular model for the generation of neuronal polarity

Bioessays

The role of local actin instability in axon formation

Science

The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo

J. Neurosci

Rac1-dependent actin filament organization in growth cones is necessary for beta1-integrin-mediated advance but not for growth on poly-d-lysine

J. Neurobiol.

Small GTPases in axon outgrowth

Perspect. Dev. Neurobiol.

Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis

Neuron

Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42

Neuron

Multiple roles of EPH receptors and ephrins in neural development

Nat. Rev. Neurosci.

Eph receptors and ephrins

Review
The role of Rho GTPases and associated kinases in regulating neurite outgrowth