scholarly journals Functional Redundancy of Cyclase-Associated Proteins CAP1 and CAP2 in Differentiating Neurons

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1525
Author(s):  
Felix Schneider ◽  
Isabell Metz ◽  
Sharof Khudayberdiev ◽  
Marco B. Rust
Keyword(s):  
Growth Cone ◽  
Hippocampal Neurons ◽  
Expression Patterns ◽  
Functional Redundancy ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Brain Anatomy ◽  
Compensatory Mechanisms ◽  
Neuron Differentiation ◽  
Associated Proteins

Cyclase-associated proteins (CAPs) are evolutionary-conserved actin-binding proteins with crucial functions in regulating actin dynamics, the spatiotemporally controlled assembly and disassembly of actin filaments (F-actin). Mammals possess two family members (CAP1 and CAP2) with different expression patterns. Unlike most other tissues, both CAPs are expressed in the brain and present in hippocampal neurons. We recently reported crucial roles for CAP1 in growth cone function, neuron differentiation, and neuron connectivity in the mouse brain. Instead, CAP2 controls dendritic spine morphology and synaptic plasticity, and its dysregulation contributes to Alzheimer’s disease pathology. These findings are in line with a model in which CAP1 controls important aspects during neuron differentiation, while CAP2 is relevant in differentiated neurons. We here report CAP2 expression during neuron differentiation and its enrichment in growth cones. We therefore hypothesized that CAP2 is relevant not only in excitatory synapses, but also in differentiating neurons. However, CAP2 inactivation neither impaired growth cone morphology and motility nor neuron differentiation. Moreover, CAP2 mutant mice did not display any obvious changes in brain anatomy. Hence, differently from CAP1, CAP2 was dispensable for neuron differentiation and brain development. Interestingly, overexpression of CAP2 rescued not only growth cone size in CAP1-deficient neurons, but also their morphology and differentiation. Our data provide evidence for functional redundancy of CAP1 and CAP2 in differentiating neurons, and they suggest compensatory mechanisms in single mutant neurons.

CAP1 and cofilin1 cooperate in neuronal actin dynamics, growth cone function and neuron connectivity

2020 ◽  
Author(s):  
Felix Schneider ◽  
Thuy-An Duong ◽  
Isabell Metz ◽  
Jannik Winkelmeier ◽  
Christian A. Hübner ◽  
...  
Keyword(s):  
Growth Cone ◽  
Hippocampal Neurons ◽  
Super Resolution ◽  
Growth Cones ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Control Growth ◽  
Cone Function ◽  
And Function ◽  
Super Resolution Microscopy

AbstractNeuron connectivity depends on growth cones that navigate axons through the developing brain. Growth cones protrude and retract actin-rich structures to sense guidance cues. These cues control local actin dynamics and steer growth cones towards attractants and away from repellents, thereby directing axon outgrowth. Hence, actin binding proteins (ABPs) moved into the focus as critical regulators of neuron connectivity. We found cyclase-associated protein 1 (CAP1), an ABP with unknown brain function, abundant in growth cones. Super-resolution microscopy and live cell imaging combined with pharmacological approaches on hippocampal neurons from gene-targeted mice revealed a crucial role for CAP1 in actin dynamics that is critical for growth cone morphology and function. Growth cone defects in mutant neurons compromised neuron differentiation and was associated with impaired neuron connectivity in CAP1 mutant brains. Mechanistically, we found that CAP1 and cofilin1 synergistically control growth cone actin dynamic and morphology. Together, we identified CAP1 as a novel actin regulator in growth cone that is relevant for neuron connectivity.

scholarly journals Platelet adhesion: Structural and functional diversity of short dystrophin and utrophins in the formation of dystrophinassociated-protein complexes related to actin dynamics

2005 ◽  
Vol 94 (12) ◽  
pp. 1203-1212 ◽  
Author(s):  
Doris Cerecedo ◽  
Dalila Martínez-Rojas ◽  
Oscar Chávez ◽  
Francisco Martínez-Pérez ◽  
Francisco García-Sierra ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Platelet Adhesion ◽  
Protein Complexes ◽  
Human Platelets ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Dynamic Cell ◽  
Associated Proteins ◽  
Coated Surfaces ◽  
Dynamic Structures

SummaryPlatelets are dynamic cell fragments that modify their shape during activation. Utrophin and dystrophins are minor actin-binding proteins present in muscle and non-muscle cytoskeleton. In the present study, we characterised the pattern of Dp71 isoforms and utrophin gene products by immunoblot in human platelets. Two new dystrophin isoforms were found, Dp71f and Dp71d, as well as the Up71 isoform and the dystrophin-associated proteins, α and β-dystrobrevins. Distribution of Dp71d/Dp71Δ110 m, Up400/Up71 and dystrophin-associated proteins in relation to the actin cytoskeleton was evaluated by confocal microscopy in both resting and platelets adhered on glass. Formation of two dystrophin-associated protein complexes (Dp71d/Dp71Δ110 m ~DAPC and Up400/Up71~DAPC) was demonstrated by co-immunoprecipitation and their distribution in relation to the actin cytoskeleton was characterised during platelet adhesion. The Dp71d/Dp71Δ110 m ~DAPC is maintained mainly at the granulomere and is associated with dynamic structures during activation by adhesion to thrombin-coated surfaces. Participation of both Dp71d/Dp71Δ110 m ~DAPC and Up400/Up71~DAPC in the biological roles of the platelets is discussed.

scholarly journals Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Elisa Savino ◽  
Romina Inès Cervigni ◽  
Miriana Povolo ◽  
Alessandra Stefanetti ◽  
Daniele Ferrante ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Transmembrane Protein ◽  
Neuronal Cell ◽  
Cell Aggregation ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Filamentous Actin

Abstract Mutations in proline-rich transmembrane protein 2 (PRRT2) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.

scholarly journals A direct proof that sole actin dynamics drive membrane deformations

2018 ◽  
Author(s):  
Camille Simon ◽  
Rémy Kusters ◽  
Valentina Caorsi ◽  
Antoine Allard ◽  
Majdouline Abou-Ghali ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Actin Polymerization ◽  
Cell Function ◽  
Turgor Pressure ◽  
Direct Proof ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Associated Proteins ◽  
Low Tension ◽  
Membrane Deformations

AbstractCell membrane deformations are crucial for proper cell function. Specialized protein assemblies initiate inward or outward membrane deformations that turn into, for example, filopodia or endocytic intermediates. Actin dynamics and actin-binding proteins are involved in this process, although their detailed role remains controversial. We show here that a dynamic, branched actin network is sufficient, in absence of any membrane-associated proteins, to initiate both inward and outward membrane deformation. With actin polymerization triggered at the membrane of liposomes, we produce inward filopodia-like structures at low tension, while outward endocytosis-like structures are robustly generated regardless of tension. Our results are reminiscent of endocytosis in mammalian cells, where actin polymerization forces are required when membrane tension is increased, and in yeast, where they are always required to overcome the opposing turgor pressure. By combining experimental observations with physical modeling, we propose a mechanism for actin-driven endocytosis under high tension or high pressure conditions.

scholarly journals Regulators of Actin Dynamics in Gastrointestinal Tract Tumors

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Konrad Steinestel ◽  
Eva Wardelmann ◽  
Wolfgang Hartmann ◽  
Inga Grünewald
Keyword(s):  
Tumor Cell ◽  
Cell Invasion ◽  
Intracellular Signaling ◽  
Expression Patterns ◽  
Leading Edge ◽  
Tumor Cell Invasion ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Surface Receptors ◽  
Cytoskeletal Dynamics

Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells.

Regulation of the Actin Cytoskeleton-Plasma Membrane Interplay by Phosphoinositides

2010 ◽  
Vol 90 (1) ◽  
pp. 259-289 ◽  
Author(s):  
Juha Saarikangas ◽  
Hongxia Zhao ◽  
Pekka Lappalainen
Keyword(s):  
Plasma Membrane ◽  
Actin Cytoskeleton ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Cell Physiology ◽  
Cortical Actin ◽  
Bar Domain ◽  
Pathogen Invasion ◽  
Associated Proteins ◽  
Continuous Dynamic

The plasma membrane and the underlying cortical actin cytoskeleton undergo continuous dynamic interplay that is responsible for many essential aspects of cell physiology. Polymerization of actin filaments against cellular membranes provides the force for a number of cellular processes such as migration, morphogenesis, and endocytosis. Plasma membrane phosphoinositides (especially phosphatidylinositol bis- and trisphosphates) play a central role in regulating the organization and dynamics of the actin cytoskeleton by acting as platforms for protein recruitment, by triggering signaling cascades, and by directly regulating the activities of actin-binding proteins. Furthermore, a number of actin-associated proteins, such as BAR domain proteins, are capable of directly deforming phosphoinositide-rich membranes to induce plasma membrane protrusions or invaginations. Recent studies have also provided evidence that the actin cytoskeleton-plasma membrane interactions are misregulated in a number of pathological conditions such as cancer and during pathogen invasion. Here, we summarize the wealth of knowledge on how the cortical actin cytoskeleton is regulated by phosphoinositides during various cell biological processes. We also discuss the mechanisms by which interplay between actin dynamics and certain membrane deforming proteins regulate the morphology of the plasma membrane.

scholarly journals Binding of microtubule-associated protein 1B to LIS1 affects the interaction between dynein and LIS1

2005 ◽  
Vol 389 (2) ◽  
pp. 333-341 ◽  
Author(s):  
Eva M. JiméNez-Mateos ◽  
Francisco Wandosell ◽  
Orly Reiner ◽  
Jesús Avila ◽  
Christian González-Billault
Keyword(s):  
Neuronal Migration ◽  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Molecular Motor ◽  
Cytoskeletal Proteins ◽  
Actin Binding ◽  
Microtubule Associated Proteins ◽  
Neural Processes ◽  
Associated Proteins ◽  
Differential Binding

For neuronal migration to occur, the cell must undergo morphological changes that require modifications of the cytoskeleton. Several different MAPs (microtubule-associated proteins) or actin-binding proteins are proposed to be involved in the migration of neurons. Therefore we have specifically analysed how two members of the MAP family, MAP1B and LIS1 (lissencephaly-related protein 1), interact with one another and participate in neuronal migration. Our results indicate that, in hippocampal neurons, MAP1B and LIS1 co-localize, associate and interact with each another. The interaction between these two MAPs is regulated by the phosphorylation of MAP1B. Furthermore, this interaction interferes with the association between LIS1 and the microtubule-dependent molecular motor, dynein. Clearly, the differential binding of these cytoskeletal proteins could regulate the functions attributed to the LIS1–dynein complex, including those related to extension of the neural processes necessary for neuronal migration.

scholarly journals Cofilin and Neurodegeneration: New Functions for an Old but Gold Protein

2021 ◽  
Vol 11 (7) ◽  
pp. 954
Author(s):  
Tamara Lapeña-Luzón ◽  
Laura R. Rodríguez ◽  
Vicent Beltran-Beltran ◽  
Noelia Benetó ◽  
Federico V. Pallardó ◽  
...  
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Growth Cone ◽  
Mitochondrial Function ◽  
Dendritic Spine ◽  
Cell Biology ◽  
Regulatory Mechanisms ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Neuronal Growth Cone

Cofilin is an actin-binding protein that plays a major role in the regulation of actin dynamics, an essential cellular process. This protein has emerged as a crucial molecule for functions of the nervous system including motility and guidance of the neuronal growth cone, dendritic spine organization, axonal branching, and synaptic signalling. Recently, other important functions in cell biology such as apoptosis or the control of mitochondrial function have been attributed to cofilin. Moreover, novel mechanisms of cofilin function regulation have also been described. The activity of cofilin is controlled by complex regulatory mechanisms, with phosphorylation being the most important, since the addition of a phosphate group to cofilin renders it inactive. Due to its participation in a wide variety of key processes in the cell, cofilin has been related to a great variety of pathologies, among which neurodegenerative diseases have attracted great interest. In this review, we summarized the functions of cofilin and its regulation, emphasizing how defects in these processes have been related to different neurodegenerative diseases.

The metalloproteinase ADAM10 is required for retinal ganglion cell axon guidance in the developing visual systems

2007 ◽  
Vol 30 (4) ◽  
pp. 77
Author(s):  
Y. Y. Chen ◽  
C. L. Hehr ◽  
K. Atkinson-Leadbeater ◽  
J. C. Hocking ◽  
S. McFarlane
Keyword(s):  
Ganglion Cell ◽  
Axon Guidance ◽  
Retinal Ganglion Cell ◽  
Growth Cone ◽  
Expression Patterns ◽  
Optic Tract ◽  
Axon Growth ◽  
Proteolytic Processing ◽  
Retinal Ganglion

Background: The growth cone interprets cues in its environment in order to reach its target. We want to identify molecules that regulate growth cone behaviour in the developing embryo. We investigated the role of A disintegrin and metalloproteinase 10 (ADAM10) in axon guidance in the developing visual system of African frog, Xenopus laevis. Methods: We first examined the expression patterns of adam10 mRNA by in situ hybridization. We then exposed the developing optic tract to an ADAM10 inhibitor, GI254023X, in vivo. Lastly, we inhibited ADAM10 function in diencephalic neuroepithelial cells (through which retinal ganglion cell (RGC) axons extend) or RGCs by electroporating or transfecting an ADAM10 dominant negative (dn-adam10). Results: We show that adam10 mRNA is expressed in the dorsal neuroepithelium over the time RGC axons extend towards their target, the optic tectum. Second, pharmacological inhibition of ADAM10 in an in vivo exposed brain preparation causes the failure of RGC axons to recognize their target at low concentrations (0.5, 1 μM), and the failure of the axons to make a caudal turn in the mid-diencephalon at higher concentration (5 μM). Thus, ADAM10 function is required for RGC axon guidance at two key guidance decisions. Finally, molecular inhibition of ADAM10 function by electroporating dn-adam10 in the brain neuroepithelium causes defects in RGC axon target recognition (57%) and/or defects in caudal turn (12%), as seen with the pharmacological inhibitor. In contrast, molecular inhibition of ADAM10 within the RGC axons has no effect. Conclusions: These data argue strongly that ADAM10 acts cell non-autonomously within the neuroepithelium to regulate the guidance of RGC axons. This study shows for the first time that a metalloproteinase acts in a cell non-autonomous fashion to direct vertebrate axon growth. It will provide important insights into candidate molecules that could be used to reform nerve connections if destroyed because of injury or disease. References Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000; 289(5483):1360-5. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 2005; 123(2):291-304. Pan D, Rubin GM. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 1997; 90(2):271-80.

scholarly journals Villin Severing Activity Enhances Actin-based Motility In Vivo

2007 ◽  
Vol 18 (3) ◽  
pp. 827-838 ◽  
Author(s):  
Céline Revenu ◽  
Matthieu Courtois ◽  
Alphée Michelot ◽  
Cécile Sykes ◽  
Daniel Louvard ◽  
...  
Keyword(s):  
Shigella Flexneri ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Loss Of Function ◽  
Mesenchymal Transition ◽  
Capping Protein ◽  
Function Strategy ◽  
In Cells

Villin, an actin-binding protein associated with the actin bundles that support microvilli, bundles, caps, nucleates, and severs actin in a calcium-dependant manner in vitro. We hypothesized that the severing activity of villin is responsible for its reported role in enhancing cell plasticity and motility. To test this hypothesis, we chose a loss of function strategy and introduced mutations in villin based on sequence comparison with CapG. By pyrene-actin assays, we demonstrate that this mutant has a strongly reduced severing activity, whereas nucleation and capping remain unaffected. The bundling activity and the morphogenic effects of villin in cells are also preserved in this mutant. We thus succeeded in dissociating the severing from the three other activities of villin. The contribution of villin severing to actin dynamics is analyzed in vivo through the actin-based movement of the intracellular bacteria Shigella flexneri in cells expressing villin and its severing variant. The severing mutations abolish the gain of velocity induced by villin. To further analyze this effect, we reconstituted an in vitro actin-based bead movement in which the usual capping protein is replaced by either the wild type or the severing mutant of villin. Confirming the in vivo results, villin-severing activity enhances the velocity of beads by more than two-fold and reduces the density of actin in the comets. We propose a model in which, by severing actin filaments and capping their barbed ends, villin increases the concentration of actin monomers available for polymerization, a mechanism that might be paralleled in vivo when an enterocyte undergoes an epithelio-mesenchymal transition.

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