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Mechanochemical regulation of growth cone motility.

Kerstein PC, Nichol RH, Gomez TM - Front Cell Neurosci (2015)

Bottom Line: Extensive research has shown that chemical ligands activate cell surface receptors on growth cones leading to intracellular signals that direct cytoskeletal changes.Interestingly, recent work suggests that both the mechanical properties of the environment and mechanical forces generated within growth cones influence axon guidance.In this review we discuss novel molecular mechanisms involved in growth cone force production and detection, and speculate how these processes may be necessary for the development of proper neuronal morphogenesis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Training Program, Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison Madison, WI, USA.

ABSTRACT
Neuronal growth cones are exquisite sensory-motor machines capable of transducing features contacted in their local extracellular environment into guided process extension during development. Extensive research has shown that chemical ligands activate cell surface receptors on growth cones leading to intracellular signals that direct cytoskeletal changes. However, the environment also provides mechanical support for growth cone adhesion and traction forces that stabilize leading edge protrusions. Interestingly, recent work suggests that both the mechanical properties of the environment and mechanical forces generated within growth cones influence axon guidance. In this review we discuss novel molecular mechanisms involved in growth cone force production and detection, and speculate how these processes may be necessary for the development of proper neuronal morphogenesis.

No MeSH data available.


Related in: MedlinePlus

Model of growth cone traction forces on high and low compliant substrata. Distal to the leading edge, active myosin-II generates contractile forces (Fmyosin) that pulls F-actin rearward. In addition, actin polymerization at the leading edge pushes against the plasma membrane to propel F-actin rearward (Fpolymerization). These forces integrate to drive constitutive retrograde flow (RF) of F-actin filaments at the leading edge. Stage 1 (ligand unbound). The molecular clutch is disengaged in the absence of integrin activation and clustering leading to rapid RF due to unrestrained Fmyosin and Fpolymerization. Stage 2 (ligand bound). Upon contact with extracellular matrix (ECM) proteins, integrin receptors become activated, cluster and begin recruiting adhesome-related adaptor and signaling proteins. Stage 3 (clutching). Mature point contact adhesions link with actin filaments (Fadhesion) to restrict RF and generate traction forces (Ftraction) on the substratum. Therefore, forces generated by clutching of RF are distributed between traction forces with the ECM, adhesive forces on point contacts and protrusive forces at the leading edge. Conditions that maintain clutching of RF produce robust protrusion. Stage 3a (low substratum stiffness). On soft substrata, Ftraction forces are distributed to the elastic substrata at point contact adhesions through substratum displacement, which reduces Fadhesion at point contact adhesions. Lower Fadhesion at point contacts prevents clutch slippage (breaking), leading to increased protrusion and growth cone translocation. Stage 3b (high stiffness). Little displacement of the ECM occurs on rigid substrata. Subsequently, most force of RF is transferred to Fadhesion at point contacts during clutching. The increased force on adhesions results in breaking or disassembly of point contacts via molecular stretching or activation of cellular signals. Fewer and short lived point contacts on rigid ECM disrupts clutching forces necessary for membrane protrusion and rapid outgrowth.
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Figure 3: Model of growth cone traction forces on high and low compliant substrata. Distal to the leading edge, active myosin-II generates contractile forces (Fmyosin) that pulls F-actin rearward. In addition, actin polymerization at the leading edge pushes against the plasma membrane to propel F-actin rearward (Fpolymerization). These forces integrate to drive constitutive retrograde flow (RF) of F-actin filaments at the leading edge. Stage 1 (ligand unbound). The molecular clutch is disengaged in the absence of integrin activation and clustering leading to rapid RF due to unrestrained Fmyosin and Fpolymerization. Stage 2 (ligand bound). Upon contact with extracellular matrix (ECM) proteins, integrin receptors become activated, cluster and begin recruiting adhesome-related adaptor and signaling proteins. Stage 3 (clutching). Mature point contact adhesions link with actin filaments (Fadhesion) to restrict RF and generate traction forces (Ftraction) on the substratum. Therefore, forces generated by clutching of RF are distributed between traction forces with the ECM, adhesive forces on point contacts and protrusive forces at the leading edge. Conditions that maintain clutching of RF produce robust protrusion. Stage 3a (low substratum stiffness). On soft substrata, Ftraction forces are distributed to the elastic substrata at point contact adhesions through substratum displacement, which reduces Fadhesion at point contact adhesions. Lower Fadhesion at point contacts prevents clutch slippage (breaking), leading to increased protrusion and growth cone translocation. Stage 3b (high stiffness). Little displacement of the ECM occurs on rigid substrata. Subsequently, most force of RF is transferred to Fadhesion at point contacts during clutching. The increased force on adhesions results in breaking or disassembly of point contacts via molecular stretching or activation of cellular signals. Fewer and short lived point contacts on rigid ECM disrupts clutching forces necessary for membrane protrusion and rapid outgrowth.

Mentions: Increased protrusive forces at the leading edge membrane generated by molecular clutching of F-actin RF, are balanced by adhesive (traction) forces with the cell substratum at adhesion sites (Figure 3). Traction forces with the cell substratum have been measured in migrating cells and growth cones using deformable substrata containing fluorescent tracer beads as fiducial marks (Hyland et al., 2014). Early work showed that cells migrate in the direction of the strongest substratum forces (Lo et al., 2000), which occur at focal adhesions (Plotnikov et al., 2012). In growth cones, these traction forces on the substratum are distributed within the actin-rich peripheral domain, where point contact adhesions are formed (Figure 1; Hyland et al., 2014). In response to guidance cues, localized assembly of adhesion complexes likely yield a redistribution of the traction forces on the substratum. This differential increase in traction forces on one side of the growth cone results in preferential growth in that direction. Moreover, the strength of traction forces generated by cells and growth cones increases on more rigid substrata, suggesting homeostatic regulation of force production (Chan and Odde, 2008; Koch et al., 2012). Substratum elasticity regulates integrin activity, internalization and adhesion site assembly (Du et al., 1993; Friedland et al., 2009), which likely accounts for increased traction forces at higher rigidity. Interestingly, growth cones from different neuronal types have been shown to generate different levels of substratum traction stress. For example, CNS hippocampal neurons exhibit rapid RF rates, due to decreased clutching, and can only generate modest peak traction stress. Conversely, dorsal root ganglion (DRG) neurons, which form more point contact adhesions that slow RF, can generate larger traction forces (Koch et al., 2012). These differences in traction stress may be related to the types of elastic environments CNS vs. PNS neurons encounter.


Mechanochemical regulation of growth cone motility.

Kerstein PC, Nichol RH, Gomez TM - Front Cell Neurosci (2015)

Model of growth cone traction forces on high and low compliant substrata. Distal to the leading edge, active myosin-II generates contractile forces (Fmyosin) that pulls F-actin rearward. In addition, actin polymerization at the leading edge pushes against the plasma membrane to propel F-actin rearward (Fpolymerization). These forces integrate to drive constitutive retrograde flow (RF) of F-actin filaments at the leading edge. Stage 1 (ligand unbound). The molecular clutch is disengaged in the absence of integrin activation and clustering leading to rapid RF due to unrestrained Fmyosin and Fpolymerization. Stage 2 (ligand bound). Upon contact with extracellular matrix (ECM) proteins, integrin receptors become activated, cluster and begin recruiting adhesome-related adaptor and signaling proteins. Stage 3 (clutching). Mature point contact adhesions link with actin filaments (Fadhesion) to restrict RF and generate traction forces (Ftraction) on the substratum. Therefore, forces generated by clutching of RF are distributed between traction forces with the ECM, adhesive forces on point contacts and protrusive forces at the leading edge. Conditions that maintain clutching of RF produce robust protrusion. Stage 3a (low substratum stiffness). On soft substrata, Ftraction forces are distributed to the elastic substrata at point contact adhesions through substratum displacement, which reduces Fadhesion at point contact adhesions. Lower Fadhesion at point contacts prevents clutch slippage (breaking), leading to increased protrusion and growth cone translocation. Stage 3b (high stiffness). Little displacement of the ECM occurs on rigid substrata. Subsequently, most force of RF is transferred to Fadhesion at point contacts during clutching. The increased force on adhesions results in breaking or disassembly of point contacts via molecular stretching or activation of cellular signals. Fewer and short lived point contacts on rigid ECM disrupts clutching forces necessary for membrane protrusion and rapid outgrowth.
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Related In: Results  -  Collection

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Figure 3: Model of growth cone traction forces on high and low compliant substrata. Distal to the leading edge, active myosin-II generates contractile forces (Fmyosin) that pulls F-actin rearward. In addition, actin polymerization at the leading edge pushes against the plasma membrane to propel F-actin rearward (Fpolymerization). These forces integrate to drive constitutive retrograde flow (RF) of F-actin filaments at the leading edge. Stage 1 (ligand unbound). The molecular clutch is disengaged in the absence of integrin activation and clustering leading to rapid RF due to unrestrained Fmyosin and Fpolymerization. Stage 2 (ligand bound). Upon contact with extracellular matrix (ECM) proteins, integrin receptors become activated, cluster and begin recruiting adhesome-related adaptor and signaling proteins. Stage 3 (clutching). Mature point contact adhesions link with actin filaments (Fadhesion) to restrict RF and generate traction forces (Ftraction) on the substratum. Therefore, forces generated by clutching of RF are distributed between traction forces with the ECM, adhesive forces on point contacts and protrusive forces at the leading edge. Conditions that maintain clutching of RF produce robust protrusion. Stage 3a (low substratum stiffness). On soft substrata, Ftraction forces are distributed to the elastic substrata at point contact adhesions through substratum displacement, which reduces Fadhesion at point contact adhesions. Lower Fadhesion at point contacts prevents clutch slippage (breaking), leading to increased protrusion and growth cone translocation. Stage 3b (high stiffness). Little displacement of the ECM occurs on rigid substrata. Subsequently, most force of RF is transferred to Fadhesion at point contacts during clutching. The increased force on adhesions results in breaking or disassembly of point contacts via molecular stretching or activation of cellular signals. Fewer and short lived point contacts on rigid ECM disrupts clutching forces necessary for membrane protrusion and rapid outgrowth.
Mentions: Increased protrusive forces at the leading edge membrane generated by molecular clutching of F-actin RF, are balanced by adhesive (traction) forces with the cell substratum at adhesion sites (Figure 3). Traction forces with the cell substratum have been measured in migrating cells and growth cones using deformable substrata containing fluorescent tracer beads as fiducial marks (Hyland et al., 2014). Early work showed that cells migrate in the direction of the strongest substratum forces (Lo et al., 2000), which occur at focal adhesions (Plotnikov et al., 2012). In growth cones, these traction forces on the substratum are distributed within the actin-rich peripheral domain, where point contact adhesions are formed (Figure 1; Hyland et al., 2014). In response to guidance cues, localized assembly of adhesion complexes likely yield a redistribution of the traction forces on the substratum. This differential increase in traction forces on one side of the growth cone results in preferential growth in that direction. Moreover, the strength of traction forces generated by cells and growth cones increases on more rigid substrata, suggesting homeostatic regulation of force production (Chan and Odde, 2008; Koch et al., 2012). Substratum elasticity regulates integrin activity, internalization and adhesion site assembly (Du et al., 1993; Friedland et al., 2009), which likely accounts for increased traction forces at higher rigidity. Interestingly, growth cones from different neuronal types have been shown to generate different levels of substratum traction stress. For example, CNS hippocampal neurons exhibit rapid RF rates, due to decreased clutching, and can only generate modest peak traction stress. Conversely, dorsal root ganglion (DRG) neurons, which form more point contact adhesions that slow RF, can generate larger traction forces (Koch et al., 2012). These differences in traction stress may be related to the types of elastic environments CNS vs. PNS neurons encounter.

Bottom Line: Extensive research has shown that chemical ligands activate cell surface receptors on growth cones leading to intracellular signals that direct cytoskeletal changes.Interestingly, recent work suggests that both the mechanical properties of the environment and mechanical forces generated within growth cones influence axon guidance.In this review we discuss novel molecular mechanisms involved in growth cone force production and detection, and speculate how these processes may be necessary for the development of proper neuronal morphogenesis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Training Program, Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison Madison, WI, USA.

ABSTRACT
Neuronal growth cones are exquisite sensory-motor machines capable of transducing features contacted in their local extracellular environment into guided process extension during development. Extensive research has shown that chemical ligands activate cell surface receptors on growth cones leading to intracellular signals that direct cytoskeletal changes. However, the environment also provides mechanical support for growth cone adhesion and traction forces that stabilize leading edge protrusions. Interestingly, recent work suggests that both the mechanical properties of the environment and mechanical forces generated within growth cones influence axon guidance. In this review we discuss novel molecular mechanisms involved in growth cone force production and detection, and speculate how these processes may be necessary for the development of proper neuronal morphogenesis.

No MeSH data available.


Related in: MedlinePlus