scholarly journals Matrix elasticity gradients guide neuronal polarity by controlling microtubule network mobility

2021 ◽  
Author(s):  
Mithila Burute ◽  
Klara I Jansen ◽  
Marko Mihajlovic ◽  
Tina Vermonden ◽  
Lukas Kapitein
Keyword(s):  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Neuronal Polarity ◽  
Network Mobility ◽  
Microtubule Network ◽  
Polarized Transport ◽  
Axon Specification ◽  
Necessary And Sufficient ◽  
Cytoskeletal Rearrangements ◽  
Neuronal Polarization

Neuronal polarization and axon specification depend on extracellular cues, intracellular signaling, cytoskeletal rearrangements and polarized transport, but the interplay between these processes has remained unresolved. The polarized transport of kinesin-1 into a specific neurite is an early marker for axon identity, but the mechanisms that govern neurite selection and polarized transport are unknown. We show that extracellular elasticity gradients control polarized transport and axon specification, mediated by Rho-GTPases whose local activation is necessary and sufficient for polarized transport. Selective Kinesin-1 accumulation furthermore depends on differences in microtubule network mobility between neurites and local control over this mobility is necessary and sufficient for proper polarization, as shown using optogenetic anchoring of microtubules. Together, these results explain how mechanical cues can instruct polarized transport and axon specification.

scholarly journals Extracellular and Intracellular Signaling for Neuronal Polarity

2015 ◽  
Vol 95 (3) ◽  
pp. 995-1024 ◽  
Author(s):  
Takashi Namba ◽  
Yasuhiro Funahashi ◽  
Shinichi Nakamuta ◽  
Chundi Xu ◽  
Tetsuya Takano ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Culture Conditions ◽  
The Body ◽  
Neuronal Polarity ◽  
Cultured Neurons ◽  
Extrinsic Factors ◽  
Major Question ◽  
Neuronal Polarization

Neurons are one of the highly polarized cells in the body. One of the fundamental issues in neuroscience is how neurons establish their polarity; therefore, this issue fascinates many scientists. Cultured neurons are useful tools for analyzing the mechanisms of neuronal polarization, and indeed, most of the molecules important in their polarization were identified using culture systems. However, we now know that the process of neuronal polarization in vivo differs in some respects from that in cultured neurons. One of the major differences is their surrounding microenvironment; neurons in vivo can be influenced by extrinsic factors from the microenvironment. Therefore, a major question remains: How are neurons polarized in vivo? Here, we begin by reviewing the process of neuronal polarization in culture conditions and in vivo. We also survey the molecular mechanisms underlying neuronal polarization. Finally, we introduce the theoretical basis of neuronal polarization and the possible involvement of neuronal polarity in disease and traumatic brain injury.

scholarly journals Tuba activates Cdc42 during neuronal polarization downstream of the small GTPase Rab8a

2019 ◽  
Author(s):  
Pamela J. Urrutia ◽  
Felipe Bodaleo ◽  
Daniel A. Bórquez ◽  
Victoria Rozes-Salvador ◽  
Cristopher Villablanca ◽  
...  
Keyword(s):  
Small Gtpases ◽  
Membrane Dynamics ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Neuronal Polarity ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Molecular Determinants ◽  
Axon Specification ◽  
Neuronal Polarization

ABSTRACTThe acquisition of neuronal polarity is a complex molecular process that involves several different cellular mechanisms that need to be finely coordinated to define the somatodendritic and axonal compartments. Amongst such mechanisms, cytoskeleton and membrane dynamics control both the morphological transitions that define neuronal polarity acquisition as well as provide molecular determinants to specific sites in neurons at a defined time point. Small GTPases from the Rab and Rho families are well known molecular determinants of neuronal differentiation. However, during axon specification, a molecular link that couples proteins from these two families has yet to be identified. In this paper, we describe the role of Tuba, a Cdc42-specific guanine nucleotide-exchange factor (GEF), in neuronal polarity through a Rab8a-dependent mechanism. Rab8a or Tuba gain-of-function generates neurons with supernumerary axons whereas Rab8a or Tuba loss-of-function abrogated axon specification, phenocopying the well-established effect of Cdc42 on neuronal polarity. Neuronal polarization associated to Rab8a is also evidenced in vivo, since a dominant negative version of Rab8a severely impaired neuronal migration.Remarkably, Rab8a activates Cdc42 in a Tuba-dependent manner, and dominant negative mutants of both GTPases reciprocally prevent the effect over polarity acquisition in the gain-of-function scenarios. Our results strongly suggest that a positive feedback loop linking Rab8a and Cdc42 activities via Tuba, is a primary event in neuronal polarization. In addition, we identified the GEF responsible for Cdc42 activation that is essential to specify axons in cultured neurons.

scholarly journals TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays

Neuron ◽  
2015 ◽  
Vol 88 (6) ◽  
pp. 1208-1226 ◽  
Author(s):  
Sam F.B. van Beuningen ◽  
Lena Will ◽  
Martin Harterink ◽  
Anaël Chazeau ◽  
Eljo Y. van Battum ◽  
...  
Keyword(s):  
Neuronal Polarity ◽  
Axon Specification

scholarly journals Control of cortical cytoskeleton-membrane interaction by RhoA regulates peripheral nerve myelination

2021 ◽  
Author(s):  
Ana I. Seixas ◽  
Miguel R. G. Morais ◽  
Cord Brakebusch ◽  
Jo&atildeo B. Relvas
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Cell Interaction ◽  
Actin Dynamics ◽  
Specific Gene ◽  
Cortical Actin ◽  
Membrane Attachment ◽  
Cytoskeleton Dynamics

Bidirectional transmission of mechanical and biochemical signals is integral to cell-environment communication and underlies the function of Schwann cells, the myelinating glia of the peripheral nervous system. As major integrators of "outside-in" signaling, Rho GTPases link actin cytoskeleton dynamics with cellular architecture to regulate adhesion and cell deformation. Using Schwann cell-specific gene inactivation, we discovered that RhoA promotes the initiation of myelination, axonal wrapping and axial spreading of Schwann cells, and is later required to restrict myelin growth in peripheral nerves. These effects are mediated by modulation of actomyosin contractility, actin dynamics and cortical actin-membrane attachment, which collectively couple tensional forces to intracellular signaling that regulate axon-Schwann cell interaction and myelin synthesis. This work establishes RhoA as an intrinsic regulator of a biomechanical response that controls the switch of Schwann cells towards the myelinating and the homeostatic states.

TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG

2000 ◽  
Vol 113 (4) ◽  
pp. 729-739 ◽  
Author(s):  
A. Blangy ◽  
E. Vignal ◽  
S. Schmidt ◽  
A. Debant ◽  
C. Gauthier-Rouviere ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Active Sites ◽  
Dominant Negative ◽  
Signaling Cascade ◽  
Microtubule Network ◽  
Cell Structures ◽  
Dependent Cell

Rho GTPases regulate the morphology of cells stimulated by extracellular ligands. Their activation is controlled by guanine exchange factors (GEF) that catalyze their binding to GTP. The multidomain Trio protein represents an emerging class of Ρ regulators that contain two GEF domains of distinct specificities. We report here the characterization of Rho signaling pathways activated by the N-terminal GEF domain of Trio (TrioD1). In fibroblasts, TrioD1 triggers the formation of particular cell structures, similar to those elicited by RhoG, a GTPase known to activate both Rac1 and Cdc42Hs. In addition, the activity of TrioD1 requires the microtubule network and relocalizes RhoG at the active sites of the plasma membrane. Using a classical in vitro exchange assay, TrioD1 displays a higher GEF activity on RhoG than on Rac1. In fibroblasts, expression of dominant negative RhoG mutants totally abolished TrioD1 signaling, whereas dominant negative Rac1 and Cdc42Hs only led to partial and complementary inhibitions. Finally, expression of a Rho Binding Domain that specifically binds RhoG(GTP) led to the complete abolition of TrioD1 signaling, which strongly supports Rac1 not being activated by TrioD1 in vivo. These data demonstrate that Trio controls a signaling cascade that activates RhoG, which in turn activates Rac1 and Cdc42Hs.

Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes

2002 ◽  
Vol 115 (2) ◽  
pp. 433-443
Author(s):  
Alix Delaguillaumie ◽  
Cécile Lagaudrière-Gesbert ◽  
Michel R. Popoff ◽  
Hélène Conjeaud
Keyword(s):  
T Lymphocytes ◽  
Tyrosine Kinases ◽  
Rho Gtpases ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Rho Gtpase ◽  
Morphological Changes ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Cytoskeletal Rearrangements

Activation of T lymphocytes requires the engagement of the T-cell receptor and costimulation molecules through cell-to-cell contacts. The tetraspanin CD82 has previously been shown to act as a cytoskeleton-dependent costimulation molecule. We show here that CD82 engagement leads to the tyrosine phosphorylation and association of both the Rho GTPases guanosine exchange factor Vav1 and adapter protein SLP76, suggesting that Rho GTPases participate in CD82 signaling. Indeed, broad inactivation of all Rho GTPases, or a specific blockade of RhoA, Rac1 or Cdc42, inhibited the morphological changes linked to CD82 engagement but failed to modulate the inducible association of CD82 with the actin network. Rho GTPase inactivation, as well as actin depolymerization, reduced the ability of CD82 to phosphorylate Vav and SLP76 and to potentiate the phosphorylation of two early TcR signaling intermediates: the tyrosine kinases ZAP70 and membrane adapter LAT. Taken together, this suggests that an amplification loop, via early Vav and SLP76 phosphorylations and Rho-GTPases activation, is initiated by CD82 association with the cytoskeleton, which permits cytoskeletal rearrangements and costimulatory activity. Moreover, the involvement of CD82 in the formation of the immunological synapse is strongly suggested by its accumulation at the site of TcR engagement. This novel link between a tetraspanin and the Rho GTPase cascade could explain why tetraspanins, which are known to form heterocomplexes, are involved in cell activation, adhesion, growth and metastasis.

scholarly journals CAMSAP1 breaks the homeostatic microtubule network to instruct neuronal polarity

2020 ◽  
Vol 117 (36) ◽  
pp. 22193-22203
Author(s):  
Zhengrong Zhou ◽  
Honglin Xu ◽  
Yuejia Li ◽  
Mengge Yang ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Decisive Role ◽  
Decisive Factor ◽  
Neuronal Polarity ◽  
Asymmetric Distribution ◽  
Microtubule Network ◽  
Radial Migration ◽  
Identification Process ◽  
Establishment Process

The establishment of axon/dendrite polarity is fundamental for neurons to integrate into functional circuits, and this process is critically dependent on microtubules (MTs). In the early stages of the establishment process, MTs in axons change dramatically with the morphological building of neurons; however, how the MT network changes are triggered is unclear. Here we show that CAMSAP1 plays a decisive role in the neuronal axon identification process by regulating the number of MTs. Neurons lacking CAMSAP1 form a multiple axon phenotype in vitro, while the multipolar-bipolar transition and radial migration are blocked in vivo. We demonstrate that the polarity regulator MARK2 kinase phosphorylates CAMSAP1 and affects its ability to bind to MTs, which in turn changes the protection of MT minus-ends and also triggers asymmetric distribution of MTs. Our results indicate that the polarized MT network in neurons is a decisive factor in establishing axon/dendritic polarity and is initially triggered by polarized signals.

scholarly journals Vav1 and Ly-GDI Two Regulators of Rho GTPases, Function Cooperatively as Signal Transducers in T Cell Antigen Receptor-induced Pathways

2002 ◽  
Vol 277 (51) ◽  
pp. 50121-50130 ◽  
Author(s):  
Maya Groysman ◽  
Idit Hornstein ◽  
Andres Alcover ◽  
Shulamit Katzav
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Calcium Mobilization ◽  
Hematopoietic Cell ◽  
Fine Tuning ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Activated T Cells

The Rho family GTPases are pivotal for T cell signaling; however, the regulation of these proteins is not fully known. One well studied regulator of Rho GTPases is Vav1; a hematopoietic cell-specific guanine nucleotide exchange factor critical for signaling in T cells, including stimulation of the nuclear factor of activated T cells (NFAT). Surprisingly, Vav1 associates with Ly-GDI, a hematopoietic cell-specific guanine nucleotide dissociation inhibitor of Rac. Here, we studied the functional significance of the interaction between Vav1 and Ly-GDI in T cells. Upon organization of the immunological synapse, both Ly-GDI and Vav1 relocalize to T cell extensions in contact with the antigen-presenting cell. Ly-GDI is phosphorylated on tyrosine residues following T cell receptor stimulation, and it associates with the Src homology 2 region of an adapter protein, Shc. In addition, the interaction between Ly-GDI and Vav1 requires tyrosine phosphorylation. Overexpression of Ly-GDI alone is inhibitory to NFAT stimulation and calcium mobilization. However, when co-expressed with Vav1, Ly-GDI enhances Vav1 induction of NFAT activation, phospholipase Cγ phosphorylation, and calcium mobilization. Moreover, Ly-GDI does not alter the regulation of these phenomena when coexpressed with oncogenic Vav1. Since oncogenic Vav1 does not bind Ly-GDI, this suggests that the functional cooperativity of Ly-GDI and Vav1 is dependent upon their association. Thus, our data suggest that the interaction of Vav1 and Ly-GDI creates a fine tuning mechanism for the regulation of intracellular signaling pathways leading to NFAT stimulation.

scholarly journals Microtubule stabilization specifies initial neuronal polarization

2008 ◽  
Vol 180 (3) ◽  
pp. 619-632 ◽  
Author(s):  
Harald Witte ◽  
Dorothee Neukirchen ◽  
Frank Bradke
Keyword(s):  
Hippocampal Neurons ◽  
Glycogen Synthase ◽  
Initial Step ◽  
Microtubule Dynamics ◽  
Neuronal Polarity ◽  
Low Doses ◽  
Microtubule Stabilization ◽  
Physiological Signal ◽  
Microtubule Stability ◽  
Neuronal Polarization

Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polarized cells. Loss of polarity or formation of multiple axons after manipulation of neuronal polarity regulators, synapses of amphids defective (SAD) kinases, and glycogen synthase kinase-3β correlates with characteristic changes in microtubule turnover. Consistently, changing the microtubule dynamics is sufficient to alter neuronal polarization. Application of low doses of the microtubule-destabilizing drug nocodazole selectively reduces the formation of future dendrites. Conversely, low doses of the microtubule-stabilizing drug taxol shift polymerizing microtubules from neurite shafts to process tips and lead to the formation of multiple axons. Finally, local stabilization of microtubules using a photoactivatable analogue of taxol induces axon formation from the activated area. Thus, local microtubule stabilization in one neurite is a physiological signal specifying neuronal polarization.

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