Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance

Baba, Kenichiro; Yoshida, Wataru; Toriyama, Minoru; Shimada, Tadayuki; Manning, Colleen; Saito, Michiko; Kohno, Kenji; Trimmer, James S.; Watanabe, Rikiya; Inagaki, Naoyuki

doi:10.7554/elife.34593

Cited by 35 publications

(96 citation statements)

References 80 publications

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“…We prioritized known axonogenesis genes displaying an obvious isoform switch but insignificant gene-level change and therefore focused on Shtn1 (Shootin1). Originally discovered as a neuronal polarization-induced gene (Toriyama et al, 2006), Shtn1 KO mice display agenesis of multiple axonal tracts (Baba et al, 2018). The originally identified SHTN1 protein is the short isoform (SHTN1S), which skips exons 15 and 16.…”

Section: Shtn1 Switches Isoform Expression During Early Axonogenesismentioning

confidence: 99%

Axonogenesis Is Coordinated by Neuron-Specific Alternative Splicing Programming and Splicing Regulator PTBP2

Zhang

Ergin

Lin

et al. 2019

Neuron

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Section: Shtn1 Switches Isoform Expression During Early Axonogenesismentioning

confidence: 99%

Axonogenesis Is Coordinated by Neuron-Specific Alternative Splicing Programming and Splicing Regulator PTBP2

Zhang

Ergin

Lin

et al. 2019

Neuron

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“…However, the possibility that Taken together, our observations suggest that Fmn2 regulates the clutch activity at adhesion sites and thereby mediates growth cone translocation. For haptotactic responses of growth cones, the local differences in clutch activity in response to external cues are believed to steer growth cones and impart directionality (Baba et al 2018). In Xenopus spinal neurons, local changes in F-actin retrograde flow at point contacts have been shown to mediate axon guidance (Santiago-Medina et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Fmn2 regulates growth cone motility by mediating a molecular clutch to generate traction forces

Ghate

Mutalik

Sthanam

et al. 2020

Preprint

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Growth cone -mediated axonal outgrowth and accurate synaptic targeting are central to brain morphogenesis. Translocation of the growth cone necessitates mechanochemical regulation of cell -extracellular matrix interactions and the generation of propulsive traction forces onto the growth environment. However, the molecular mechanisms subserving force generation by growth cones remain poorly characterized. The formin family member, Fmn2, has been identified earlier as a regulator of growth cone motility. Here, we explore the mechanisms underlying Fmn2 function in the growth cone. Using multiple components of the adhesion complexes, we show that Fmn2 regulates point contact stability. Analysis of F-actin retrograde flow reveals that Fmn2 functions as a clutch molecule and mediates the coupling of the actin cytoskeleton to the growth substrate, via the point contact adhesion complex. Using traction force microscopy, we show that the Fmn2-mediated clutch function is necessary for the generation of traction stresses by neurons. Our findings suggest that Fmn2, a protein associated with neurodevelopmental and neurodegenerative disorders, is a key regulator of a molecular clutch activity and consequently motility of neuronal growth cones.

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“…The tip of an extending axon also bears a growth cone ( Lowery and Van Vactor, 2009 ), and axonal growth cones produce traction forces for axon outgrowth and guidance ( Chan and Odde, 2008 ; Koch et al, 2012 ; Abe et al, 2018 ; Baba et al, 2018 ). Decades of analyses of axonal growth cones have revealed a key machinery to generate traction forces for growth cone migration.…”

Section: Forces For Leading Process Extensionmentioning

confidence: 99%

“…Shootin1a interacts with F-actin retrograde flow through its association with the F-actin-interacting protein cortactin ( Kubo et al, 2015 ). Shootin1a also interacts with the cell adhesion molecule L1-CAM ( Baba et al, 2018 ), which binds to the ECM protein laminin ( Abe et al, 2018 ) as well as to L1-CAM expressed on neighboring cells ( Lemmon et al, 1989 ), thereby mechanically coupling the F-actin retrograde flow with the adhesive substrates. The shootin1a-mediated actin–adhesion coupling generates traction forces for axon outgrowth ( Kubo et al, 2015 ) and axon guidance induced by diffusible and substrate-bound chemical cues ( Abe et al, 2018 ; Baba et al, 2018 ).…”

Section: Forces For Leading Process Extensionmentioning

confidence: 99%

“…Shootin1a also interacts with the cell adhesion molecule L1-CAM ( Baba et al, 2018 ), which binds to the ECM protein laminin ( Abe et al, 2018 ) as well as to L1-CAM expressed on neighboring cells ( Lemmon et al, 1989 ), thereby mechanically coupling the F-actin retrograde flow with the adhesive substrates. The shootin1a-mediated actin–adhesion coupling generates traction forces for axon outgrowth ( Kubo et al, 2015 ) and axon guidance induced by diffusible and substrate-bound chemical cues ( Abe et al, 2018 ; Baba et al, 2018 ). N-cadherin–catenin complexes were also reported to mediate actin–adhesion coupling at the axonal growth cone ( Bard et al, 2008 ; Garcia et al, 2015 ).…”

Section: Forces For Leading Process Extensionmentioning

confidence: 99%

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Forces to Drive Neuronal Migration Steps

Minegishi

Inagaki

2020

Front. Cell Dev. Biol.

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To establish and maintain proper brain architecture and elaborate neural networks, neurons undergo massive migration. As a unique feature of their migration, neurons move in a saltatory manner by repeating two distinct steps: extension of the leading process and translocation of the cell body. Neurons must therefore generate forces to extend the leading process as well as to translocate the cell body. In addition, neurons need to switch these forces alternately in order to orchestrate their saltatory movement. Recent studies with mechanobiological analyses, including traction force microscopy, cell detachment analyses, live-cell imaging, and loss-of-function analyses, have begun to reveal the forces required for these steps and the molecular mechanics underlying them. Spatiotemporally organized forces produced between cells and their extracellular environment, as well as forces produced within cells, play pivotal roles to drive these neuronal migration steps. Traction force produced by the leading process growth cone extends the leading processes. On the other hand, mechanical tension of the leading process, together with reduction in the adhesion force at the rear and the forces to drive nucleokinesis, translocates the cell body. Traction forces are generated by mechanical coupling between actin filament retrograde flow and the extracellular environment through clutch and adhesion molecules. Forces generated by actomyosin and dynein contribute to the nucleokinesis. In addition to the forces generated in cell-intrinsic manners, external forces provided by neighboring migratory cells coordinate cell movement during collective migration. Here, we review our current understanding of the forces that drive neuronal migration steps and describe the molecular machineries that generate these forces for neuronal migration.

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Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance

Cited by 35 publications

References 80 publications

Axonogenesis Is Coordinated by Neuron-Specific Alternative Splicing Programming and Splicing Regulator PTBP2

Axonogenesis Is Coordinated by Neuron-Specific Alternative Splicing Programming and Splicing Regulator PTBP2

Fmn2 regulates growth cone motility by mediating a molecular clutch to generate traction forces

Forces to Drive Neuronal Migration Steps

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