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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

Point contact adhesion dynamics in neuronal growth cones. (A) Inverted contrast images of a Xenopus growth cone expressing Paxillin-GFP captured every 1 min over a 4 min period using TIRF microscopy. The arrows and black boxes denote the adhesions viewed in (B) and (C). (B,C) Images of individual adhesions are displayed at 15 s intervals. The arrows indicate the first and last frames of specific paxillin-GFP puncta. This figure was created with an original timelapse captured for demonstration purposes in this manuscript using techniques previously described (Woo et al., 2009; Myers and Gomez, 2011). Scale bar, 5 μm for all panels.
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Figure 2: Point contact adhesion dynamics in neuronal growth cones. (A) Inverted contrast images of a Xenopus growth cone expressing Paxillin-GFP captured every 1 min over a 4 min period using TIRF microscopy. The arrows and black boxes denote the adhesions viewed in (B) and (C). (B,C) Images of individual adhesions are displayed at 15 s intervals. The arrows indicate the first and last frames of specific paxillin-GFP puncta. This figure was created with an original timelapse captured for demonstration purposes in this manuscript using techniques previously described (Woo et al., 2009; Myers and Gomez, 2011). Scale bar, 5 μm for all panels.

Mentions: Growth cone point contact adhesions are related to fibroblast focal adhesions, which are multi-functional, macromolecular protein complexes (Smilenov et al., 1999; Bard et al., 2008; Shimada et al., 2008; Geiger et al., 2009; Giannone et al., 2009; Toriyama et al., 2013). However, much less is understood about the molecular regulation and function of growth cone adhesions, and it is likely that these adhesions serve many functions that are unique to growth cones. Point contact adhesions typically assemble within growth cone filopodia that contain parallel bundled actin, have a short lifetime, then disassemble near the base of filopodia (Figure 2). Point contact adhesions appear to require integrin engagement, as they are observed primarily in growth cones on extracellular matrix (ECM) proteins (Woo and Gomez, 2006; Myers and Gomez, 2011). The ECM contains many ligands that modulate growth cone motility, such as laminin, tenascin, fibronectin, etc. Each type of ECM ligand activates specific integrin receptors, as we have recently reviewed (Myers et al., 2011). Activation of integrins leads to recruitment of scaffolding and signaling proteins, such as talin, focal adhesion kinase (FAK), paxillin, zyxin, and α-actinin (Gomez et al., 1996; Cluzel et al., 2005; Robles and Gomez, 2006; Myers et al., 2011). In non-neuronal cells, scaffolding proteins link to actin filaments to clutch RF, which supports actin polymerization to drive protrusion of the leading edge (Smilenov et al., 1999; Giannone et al., 2009; Thievessen et al., 2013). Similar clutching of RF likely occurs at growth cone point contacts (Santiago-Medina et al., 2013) and higher density adhesions have been linked to slower RF (Koch et al., 2012). Importantly, since point contact adhesions are modulated by ECM and soluble guidance factors (Woo and Gomez, 2006; Myers and Gomez, 2011; Myers et al., 2012), it is plausible that growth cone guidance is controlled by local changes in RF. Indeed, early studies from Paul Forscher and colleagues suggested that local reduction in RF is correlated with increased growth cone motility (Lin and Forscher, 1995; Lin et al., 1996; Santiago-Medina et al., 2013). For example, reduced RF is correlated with translocation of the growth cone central domain toward areas of strong adhesion of Aplysia neurons in contact with ApCAM-coated beads (Lin and Forscher, 1995; Suter et al., 1998). While the adapter proteins that link and clutch F-actin differ between cell adhesion molecules, such as ApCAM, L1 and N-cadherin, and integrin-ECM adhesions, they both function to restrain RF and promote axon outgrowth (Lin and Forscher, 1995; Suter et al., 1998; Bard et al., 2008; Toriyama et al., 2013).


Mechanochemical regulation of growth cone motility.

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

Point contact adhesion dynamics in neuronal growth cones. (A) Inverted contrast images of a Xenopus growth cone expressing Paxillin-GFP captured every 1 min over a 4 min period using TIRF microscopy. The arrows and black boxes denote the adhesions viewed in (B) and (C). (B,C) Images of individual adhesions are displayed at 15 s intervals. The arrows indicate the first and last frames of specific paxillin-GFP puncta. This figure was created with an original timelapse captured for demonstration purposes in this manuscript using techniques previously described (Woo et al., 2009; Myers and Gomez, 2011). Scale bar, 5 μm for all panels.
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Figure 2: Point contact adhesion dynamics in neuronal growth cones. (A) Inverted contrast images of a Xenopus growth cone expressing Paxillin-GFP captured every 1 min over a 4 min period using TIRF microscopy. The arrows and black boxes denote the adhesions viewed in (B) and (C). (B,C) Images of individual adhesions are displayed at 15 s intervals. The arrows indicate the first and last frames of specific paxillin-GFP puncta. This figure was created with an original timelapse captured for demonstration purposes in this manuscript using techniques previously described (Woo et al., 2009; Myers and Gomez, 2011). Scale bar, 5 μm for all panels.
Mentions: Growth cone point contact adhesions are related to fibroblast focal adhesions, which are multi-functional, macromolecular protein complexes (Smilenov et al., 1999; Bard et al., 2008; Shimada et al., 2008; Geiger et al., 2009; Giannone et al., 2009; Toriyama et al., 2013). However, much less is understood about the molecular regulation and function of growth cone adhesions, and it is likely that these adhesions serve many functions that are unique to growth cones. Point contact adhesions typically assemble within growth cone filopodia that contain parallel bundled actin, have a short lifetime, then disassemble near the base of filopodia (Figure 2). Point contact adhesions appear to require integrin engagement, as they are observed primarily in growth cones on extracellular matrix (ECM) proteins (Woo and Gomez, 2006; Myers and Gomez, 2011). The ECM contains many ligands that modulate growth cone motility, such as laminin, tenascin, fibronectin, etc. Each type of ECM ligand activates specific integrin receptors, as we have recently reviewed (Myers et al., 2011). Activation of integrins leads to recruitment of scaffolding and signaling proteins, such as talin, focal adhesion kinase (FAK), paxillin, zyxin, and α-actinin (Gomez et al., 1996; Cluzel et al., 2005; Robles and Gomez, 2006; Myers et al., 2011). In non-neuronal cells, scaffolding proteins link to actin filaments to clutch RF, which supports actin polymerization to drive protrusion of the leading edge (Smilenov et al., 1999; Giannone et al., 2009; Thievessen et al., 2013). Similar clutching of RF likely occurs at growth cone point contacts (Santiago-Medina et al., 2013) and higher density adhesions have been linked to slower RF (Koch et al., 2012). Importantly, since point contact adhesions are modulated by ECM and soluble guidance factors (Woo and Gomez, 2006; Myers and Gomez, 2011; Myers et al., 2012), it is plausible that growth cone guidance is controlled by local changes in RF. Indeed, early studies from Paul Forscher and colleagues suggested that local reduction in RF is correlated with increased growth cone motility (Lin and Forscher, 1995; Lin et al., 1996; Santiago-Medina et al., 2013). For example, reduced RF is correlated with translocation of the growth cone central domain toward areas of strong adhesion of Aplysia neurons in contact with ApCAM-coated beads (Lin and Forscher, 1995; Suter et al., 1998). While the adapter proteins that link and clutch F-actin differ between cell adhesion molecules, such as ApCAM, L1 and N-cadherin, and integrin-ECM adhesions, they both function to restrain RF and promote axon outgrowth (Lin and Forscher, 1995; Suter et al., 1998; Bard et al., 2008; Toriyama et al., 2013).

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